Version: 3.24 (unreleased)

ClinGen

Overview

ClinGen is a National Institutes of Health (NIH)-funded resource dedicated to building a central resource that defines the clinical relevance of genes and variants for use in precision medicine and research.

Publication

Heidi L. Rehm, Ph.D., Jonathan S. Berg, M.D., Ph.D., Lisa D. Brooks, Ph.D., Carlos D. Bustamante, Ph.D., James P. Evans, M.D., Ph.D., Melissa J. Landrum, Ph.D., David H. Ledbetter, Ph.D., Donna R. Maglott, Ph.D., Christa Lese Martin, Ph.D., Robert L. Nussbaum, M.D., Sharon E. Plon, M.D., Ph.D., Erin M. Ramos, Ph.D., Stephen T. Sherry, Ph.D., and Michael S. Watson, Ph.D., for ClinGen. ClinGen The Clinical Genome Resource. N Engl J Med 2015; 372:2235-2242 June 4, 2015 DOI: 10.1056/NEJMsr1406261.

ISCA Regions

TSV Extraction

ClinGen contains only copy number variation variants, since the coordinates in ClinGen original file follow the same rule as BED format, the coordinates had to be adjusted to [BEGIN+1, END].

#bin    chrom   chromStart      chromEnd        name    score   strand  thickStart      thickEnd        attrCount       attrTags        attrVals
nsv530705       1       564405  8597804 0       1       copy_number_loss        pathogenic      False   Developmental delay AND/OR other significant developmental or morphological phenotypes
nsv530706       1       564424  3262790 0       1       copy_number_loss        pathogenic      False   Abnormal facial shape,Abnormality of cardiac morphology,Global developmental delay,Muscular hypotonia   HP:0001252,HP:0001263,HP:0001627,HP:0001999,MedGen:CN001147,MedGen:CN001157,MedGen:CN001482,MedGen:CN001810
nsv530707       1       564424  7068738 0       1       copy_number_loss        pathogenic      False   Abnormality of cardiac morphology,Cleft upper lip,Failure to thrive,Global developmental delay,Intrauterine growth retardation,Microcephaly,Short stature       HP:0000204,HP:0000252,HP:0001263,HP:0001508,HP:0001511,HP:0001627,HP:0004322,MedGen:C0349588,MedGen:C1845868,MedGen:C1853481,MedGen:C2364119,MedGen:CN000197,MedGen:CN001157,MedGen:CN001482
nsv533512       1       564435  649748  0       1       copy_number_loss        benign  False   Developmental delay AND/OR other significant developmental or morphological phenotypes
nsv931338       1       714078  4958499 0       1       copy_number_loss        pathogenic      False   Developmental delay AND/OR other significant developmental or morphological phenotypes
nsv530300       1       728138  5066371 1       0       copy_number_gain        pathogenic      False   Abnormality of cardiac morphology,Cleft palate,Global developmental delay       HP:0000175,HP:0001263,HP:0001627,MedGen:C2240378,MedGen:CN001157,MedGen:CN001482

Status levels

benign
curated benign
curated pathogenic
likely benign
likely pathogenic
path gain
path loss
pathogenic
uncertain

Parsing

We parse the ClinGen tsv file and extract the following:

chrom
chromStart (note this a 0-based coordinate)
chromEnd
attrTags
attrVals

attrTags and attrVals are comma separated lists. attrTags contains the field keys and attrVals contains the field values. We will parse the following keys from the two fields:

parent (this will be used as the ID in our JSON output)
clinical_int
validated
phenotype (this should be a string array)
phenotype_id (this should be a string array)

Observed losses and observed gains will be calculated from entries that share a common parent ID.

variants with a common parent ID and same coordinates are grouped
- calculated observed losses, observed gains for each group
- Clinical significance and validation status are collapsed using the priority strategy described below
Variants with the same parent ID can have different coordinates (mapped to hg38)
- nsv491508 : chr14:105583663-106881350 and chr14:105605043-106766076 (only one example)
- we kept both variants

Conflict Resolution

Clinical significance priority

When there are a mixture of variants belonging to the same parent ID, we will choose the most pathogenic clinical significance from the available values. i.e. if 3 samples were deemed pathogenic and 2 samples were likely pathogenic, we would list the variant as pathogenic.

Priority (high to low)

Priority
Pathogenic
Likely pathogenic
Benign
Likely benign
Uncertain significance

Validation Priority

When there are a mixture of variants belonging to same parent ID, we will set the validation status to true if any of the variants were validated.

Download URL

https://cirm.ucsc.edu/cgi-bin/hgTrackUi?db=hg19&g=iscaComposite

JSON Output

"clingen":[
   {
      "chromosome":"17",
      "begin":525,
      "end":14667519,
      "variantType":"copy_number_gain",
      "id":"nsv996083",
      "clinicalInterpretation":"pathogenic",
      "observedGains":1,
      "validated":true,
      "phenotypes":[
         "Intrauterine growth retardation"
      ],
      "phenotypeIds":[
         "HP:0001511",
         "MedGen:C1853481"
      ],
      "reciprocalOverlap":0.00131
   },
   {
      "chromosome":"17",
      "begin":45835,
      "end":7600330,
      "variantType":"copy_number_loss",
      "id":"nsv869419",
      "clinicalInterpretation":"pathogenic",
      "observedLosses":1,
      "validated":true,
      "phenotypes":[
         "Developmental delay AND/OR other significant developmental or morphological phenotypes"
      ],
      "reciprocalOverlap":0.00254
   }
]

Field	Type	Notes
clingen	object array
chromosome	string	Ensembl-style chromosome names
begin	integer	1-based position
end	integer	1-based position
variantType	string	Any of the sequence alterations defined here.
id	string	Identifier from the data source. Alternatively a VID
clinicalInterpretation	string	see possible values below
observedGains	integer	Range: 0 - (2³¹ - 1). Only used if copy_number_variation, copy_number_loss, or copy_number_gain.
observedLosses	integer	Range: 0 - (2³¹ - 1). Only used if copy_number_variation, copy_number_loss, or copy_number_gain.
validated	boolean
phenotypes	string array	Description of the phenotype.
phenotypeIds	string array	Description of the phenotype IDs.
reciprocalOverlap	floating point	Range: 0 - 1. E.g. 0.57 would indicate a 57% reciprocal overlap. Specified up to 5 decimal places (Not reported for Insertions).

clinicalInterpretation

benign
curated benign
curated pathogenic
likely benign
likely pathogenic
path gain
path loss
pathogenic
uncertain

Dosage Sensitivity Map

The Clinical Genome Resource (ClinGen) consortium is curating genes and regions of the genome to assess whether there is evidence to support that these genes/regions are dosage sensitive and should be targeted on a cytogenomic array. Illumina Connected Annotations reports these annotations for overlapping SVs.

Publication

Riggs ER, Nelson T, Merz A, Ackley T, Bunke B, Collins CD, Collinson MN, Fan YS, Goodenberger ML, Golden DM, Haglund-Hazy L, Krgovic D, Lamb AN, Lewis Z, Li G, Liu Y, Meck J, Neufeld-Kaiser W, Runke CK, Sanmann JN, Stavropoulos DJ, Strong E, Su M, Tayeh MK, Kokalj Vokac N, Thorland EC, Andersen E, Martin CL. Copy number variant discrepancy resolution using the ClinGen dosage sensitivity map results in updated clinical interpretations in ClinVar. Hum Mutat. 2018 Nov;39(11):1650-1659. doi: 10.1002/humu.23610. PMID: 30095202; PMCID: PMC7374944.

TSV Source files

Regions

#ClinGen Region Curation Results
#07 May,2019
#Genomic Locations are reported on GRCh38 (hg38): GCF_000001405.36
#https://www.ncbi.nlm.nih.gov/projects/dbvar/clingen
#to create link: https://www.ncbi.nlm.nih.gov/projects/dbvar/clingen/clingen_region.cgi?id=key
#ISCA ID    ISCA Region Name    cytoBand    Genomic Location    Haploinsufficiency Score    Haploinsufficiency Description  Haploinsufficiency PMID1    Haploinsufficiency PMID2    Haploinsufficiency PMID3    Triplosensitivity Score Triplosensitivity Description   Triplosensitivity PMID1 Triplosensitivity PMID2 Triplosensitivity PMID3 Date Last Evaluated Loss phenotype OMIM ID  Triplosensitive phenotype OMIM ID
ISCA-46299  Xp11.22 region (includes HUWE1) Xp11.22 tbd 0   No evidence available               3   Sufficient evidence for dosage pathogenicity    22840365    20655035    26692240    2018-11-19
ISCA-46295  15q13.3 recurrent region (D-CHRNA7 to BP5) (includes CHRNA7 and OTUD7A) 15q13.3 chr15:31727418-32153204 3   Sufficient evidence for dosage pathogenicity    19898479    20236110    22775350    40  Dosage sensitivity unlikely 26968334    22420048        2018-05-10
ISCA-46291  7q11.23 recurrent distal region (includes HIP1, YWHAG)  7q11.23 chr7:75528718-76433859  2   Some evidence for dosage pathogenicity  21109226    16971481        1   Little evidence for dosage pathogenicity    21109226    27867344        2018-12-31
ISCA-46290  Xp11.22p11.23 recurrent region (includes SHROOM4)   Xp11.22-p11.23  chrX: 48447780-52444264 0   No evidence available               3   Sufficient evidence for dosage pathogenicity    19716111    21418194    25425167    2017-12-14      300801

Genes

#ClinGen Gene Curation Results
#24 May,2019
#Genomic Locations are reported on GRCh37 (hg19): GCF_000001405.13
#https://www.ncbi.nlm.nih.gov/projects/dbvar/clingen
#to create link: https://www.ncbi.nlm.nih.gov/projects/dbvar/clingen/clingen_gene.cgi?sym=Gene Symbol
#Gene Symbol    Gene ID cytoBand    Genomic Location    Haploinsufficiency Score    Haploinsufficiency Description  Haploinsufficiency PMID1    Haploinsufficiency PMID2    Haploinsufficiency PMID3    Triplosensitivity Score Triplosensitivity Description   Triplosensitivity PMID1 Triplosensitivity PMID2 Triplosensitivity PMID3 Date Last Evaluated Loss phenotype OMIM ID  Triplosensitive phenotype OMIM ID
A4GALT  53947   22q13.2 chr22:43088121-43117307 30  Gene associated with autosomal recessive phenotype              0   No evidence available               2014-12-11  111400
AAGAB   79719   15q23   chr15:67493013-67547536 3   Sufficient evidence for dosage pathogenicity    23064416    23000146        0   No evidence available               2013-02-28  148600

Dosage Rating System

Rating	Possible Clinical Interpretation
0	No evidence to suggest that dosage sensitivity is associated with clinical phenotype
1	Little evidence suggesting dosage sensitivity is associated with clinical phenotype
2	Emerging evidence suggesting dosage sensitivity is associated with clinical phenotype
3	Sufficient evidence suggesting dosage sensitivity is associated with clinical phenotype
30	Gene associated with autosomal recessive phenotype
40	Dosage sensitivity unlikely

Reference: https://www.ncbi.nlm.nih.gov/projects/dbvar/clingen/help.shtml

Download URL

ftp://ftp.clinicalgenome.org/

JSON Output

"clingenDosageSensitivityMap": [{
    "chromosome": "15",
    "begin": 30900686,
    "end": 32153204,
    "haploinsufficiency": "sufficient evidence suggesting dosage sensitivity is associated with clinical phenotype",
    "triplosensitivity": "little evidence suggesting dosage sensitivity is associated with clinical phenotype",
    "reciprocalOverlap": 0.00147,
    "annotationOverlap": 0.33994
},
{
    "chromosome": "15",
    "begin": 31727418,
    "end": 32153204,
    "haploinsufficiency": "sufficient evidence suggesting dosage sensitivity is associated with clinical phenotype",
    "triplosensitivity": "dosage sensitivity unlikely",
    "reciprocalOverlap": 0.00147,
    "annotationOverlap": 1
}]

Field	Type	Notes
clingenDosageSensitivityMap	object array
chromosome	string	Ensembl-style chromosome names
begin	integer	1-based position
end	integer	1-based position
haploinsufficiency	string	see possible values below
triplosensitivity	string	(same as haploinsufficiency)
reciprocalOverlap	floating point	Range: 0 - 1. E.g. 0.57 would indicate a 57% reciprocal overlap. Specified up to 5 decimal places (Not reported for Insertions).
annotationOverlap	floating point	Range: 0 - 1. E.g. 0.57 would indicate a 57% reciprocal overlap. Specified up to 5 decimal places (Not reported for Insertions).

haploinsufficiency and triplosensitivity

no evidence to suggest that dosage sensitivity is associated with clinical phenotype
little evidence suggesting dosage sensitivity is associated with clinical phenotype
emerging evidence suggesting dosage sensitivity is associated with clinical phenotype
sufficient evidence suggesting dosage sensitivity is associated with clinical phenotype
gene associated with autosomal recessive phenotype
dosage sensitivity unlikely

Building the supplementary files

The gene dosage sensitivity .nga for Illumina Connected Annotations can be built using the SAUtils command's DosageSensitivity subcommand. The required data file is ClinGen_gene_curation_list_{ASSEMBLY}.tsv (url provided above) and its associated .version file.

NAME=ClinGen Dosage Sensitivity Map
VERSION=20211201
DATE=2021-12-01
DESCRIPTION=Dosage sensitivity map from ClinGen (dbVar)

Here is a sample run:

dotnet SAUtils.dll DosageSensitivity
---------------------------------------------------------------------------
SAUtils                                             (c) 2023 Illumina, Inc.
Stromberg, Roy, Platzer, Siddiqui, Ouyang, et al         3.21.0-0-gd2a0e953
---------------------------------------------------------------------------

USAGE: dotnet SAUtils.dll dosagesensitivity [options]
Creates a gene annotation database from dbVar data

OPTIONS:
      --tsv, -t <VALUE>      input tsv file
      --out, -o <VALUE>      output directory
      --help, -h             displays the help menu
      --version, -v          displays the version

dotnet SAUtils.dll DosageSensitivity --out SupplementaryDatabase/64/GRCh37 --tsv ClinGen_gene_curation_list_GRCh37.tsv
---------------------------------------------------------------------------
SAUtils                                             (c) 2023 Illumina, Inc.
Stromberg, Roy, Platzer, Siddiqui, Ouyang, et al         3.21.0-0-gd2a0e953
---------------------------------------------------------------------------


Time: 00:00:00.1

For building the .nsi files, we use the SAUtils command's DosageMapRegions subcommand. The required data file is ClinGen_region_curation_list_{ASSEMBLY}.tsv (url provided above) and its associated .version file.

NAME=ClinGen Dosage Sensitivity Map
VERSION=20211201
DATE=2021-12-01
DESCRIPTION=Dosage sensitivity map from ClinGen (dbVar)

Here is a sample run:

dotnet SAUtils.dll DosageMapRegions
---------------------------------------------------------------------------
SAUtils                                             (c) 2023 Illumina, Inc.
Stromberg, Roy, Platzer, Siddiqui, Ouyang, et al         3.21.0-0-gd2a0e953
---------------------------------------------------------------------------

USAGE: dotnet SAUtils.dll dosagemapregions [options]
Creates an interval annotation database from dbVar data

OPTIONS:
      --tsv, -t <VALUE>      input tsv file
      --ref, -r <filename>   input reference filename
      --out, -o <VALUE>      output directory
      --help, -h             displays the help menu
      --version, -v          displays the version

dotnet SAUtils.dll DosageMapRegions --out SupplementaryDatabase/64/GRCh37 --ref References/7/Homo_sapiens.GRCh37.Nirvana.dat --tsv ClinGen_region_curation_list_GRCh37.tsv
---------------------------------------------------------------------------
SAUtils                                             (c) 2023 Illumina, Inc.
Stromberg, Roy, Platzer, Siddiqui, Ouyang, et al         3.21.0-0-gd2a0e953
---------------------------------------------------------------------------

Writing 505 intervals to database...

Time: 00:00:00.1

You can also use SAUtils command's subcommands AutoDownloadGenerate to generate ClinGen files. To use AutoDownloadGenerate, read more in SAUtils section.

Gene-Disease Validity

The ClinGen Gene-Disease Clinical Validity curation process involves evaluating the strength of evidence supporting or refuting a claim that variation in a particular gene causes a particular disease. Illumina Connected Annotations reports these annotations for genes in the genes section of the JSON.

Publication

Strande NT, Riggs ER, Buchanan AH, et al. Evaluating the Clinical Validity of Gene-Disease Associations: An Evidence-Based Framework Developed by the Clinical Genome Resource. Am J Hum Genet. 2017;100(6):895-906. doi:10.1016/j.ajhg.2017.04.015

Source TSV

The source data comes in a CSV file that we convert to a TSV.

CLINGEN GENE VALIDITY CURATIONS
FILE CREATED: 2019-05-28
WEBPAGE: https://search.clinicalgenome.org/kb/gene-validity
+++++++++++,++++++++++++++,+++++++++++++,++++++++++++++++++,+++++++++,++++++++++++++,+++++++++++++,+++++++++++++++++++
GENE SYMBOL,GENE ID (HGNC),DISEASE LABEL,DISEASE ID (MONDO),SOP,CLASSIFICATION,ONLINE REPORT,CLASSIFICATION DATE
+++++++++++,++++++++++++++,+++++++++++++,++++++++++++++++++,+++++++++,++++++++++++++,+++++++++++++,+++++++++++++++++++
A2ML1,HGNC:23336,Noonan syndrome with multiple lentigines,MONDO_0007893,SOP5,No Reported Evidence,https://search.clinicalgenome.org/kb/gene-validity/59b87033-dd91-4f1e-aec1-c9b1f5124b16--2018-06-07T14:37:47,2018-06-07T14:37:47.175Z
A2ML1,HGNC:23336,cardiofaciocutaneous syndrome,MONDO_0015280,SOP5,No Reported Evidence,https://search.clinicalgenome.org/kb/gene-validity/fc3c41d8-8497-489b-a350-c9e30016bc6a--2018-06-07T14:31:03,2018-06-07T14:31:03.696Z
A2ML1,HGNC:23336,Costello syndrome,MONDO_0009026,SOP5,No Reported Evidence,https://search.clinicalgenome.org/kb/gene-validity/ea72ba8d-cf62-44bc-86be-da64e3848eba--2018-06-07T14:34:05,2018-06-07T14:34:05.324Z

Download URL

https://search.clinicalgenome.org/kb/downloads#section_gene-disease-validity

Conflict Resolution

Multiple Classifications

Here is an example of multiple classifications.

$ grep MONDO_0010192 ClinGen-Gene-Disease-Summary-2019-12-02.csv  | grep EDNRB
EDNRB,HGNC:3180,Waardenburg syndrome type 4A,MONDO_0010192,SOP6,Moderate,https://search.clinicalgenome.org/kb/gene-validity/d7abbd45-7915-437b-849b-dea876bfc2f5--2018-05-08T04:00:00,2018-05-08T04:00:00.000Z
EDNRB,HGNC:3180,Waardenburg syndrome type 4A,MONDO_0010192,SOP6,Limited,https://search.clinicalgenome.org/kb/gene-validity/73ee9727-60c1-40fd-830f-08c2b513d2ee--2018-05-08T04:00:00,2018-05-08T04:00:00.000Z

In such cases, we select the more severe classification.

Multiple Dates

$ grep MONDO_0016419 ClinGen-Gene-Disease-Summary-2019-12-02.csv  | grep MUTYH
MUTYH,HGNC:7527,hereditary breast carcinoma,MONDO_0016419,SOP4,No Reported Evidence,https://search.clinicalgenome.org/kb/gene-validity/9904,2017-05-24T00:00:00
MUTYH,HGNC:7527,hereditary breast carcinoma,MONDO_0016419,SOP4,No Reported Evidence,https://search.clinicalgenome.org/kb/gene-validity/9902,2017-05-25T00:00:00

If the classifications are the same, we should select the latest classification date.

JSON Output

"clingenGeneValidity":[
   {
      "diseaseId":"MONDO_0007893",
      "disease":"Noonan syndrome with multiple lentigines",
      "classification":"no reported evidence",
      "classificationDate":"2018-06-07"
   },
   {
      "diseaseId":"MONDO_0015280",
      "disease":"cardiofaciocutaneous syndrome",
      "classification":"no reported evidence",
      "classificationDate":"2018-06-07"
   }
]

Field	Type	Notes
clingenGeneValidity	object
diseaseId	string	Monarch Disease Ontology ID (MONDO)
disease	string	disease label
classification	string	see below for possible values
classificationDate	string	yyyy-MM-dd

classification

no reported evidence
disputed
limited
moderate
definitive
strong
refuted
no known disease relationship

Building the supplementary files

The gene disease validity .nga for Illumina Connected Annotations can be built using the SAUtils command's DiseaseValidity subcommand. The only required data file is Clingen-Gene-Disease-Summary-2021-12-01.tsv (url provided above) and its associated .version file.

NAME=ClinGen disease validity curations
VERSION=20211201
DATE=2021-12-01
DESCRIPTION=Disease validity curations from ClinGen (dbVar)

Here is a sample run:

 dotnet SAUtils.dll DiseaseValidity
---------------------------------------------------------------------------
SAUtils                                             (c) 2023 Illumina, Inc.
Stromberg, Roy, Platzer, Siddiqui, Ouyang, et al         3.21.0-0-gd2a0e953
---------------------------------------------------------------------------

USAGE: dotnet SAUtils.dll diseasevalidity [options]
Creates a gene annotation database from ClinGen gene validity data

OPTIONS:
      --csv, -i <VALUE>      ClinGen gene validity file path
      --cache, -c <directory>
                             input cache directory
      --ref, -r <filename>   input reference filename
      --out, -o <VALUE>      output directory
      --help, -h             displays the help menu
      --version, -v          displays the version

dotnet SAUtils.dll DiseaseValidity --tsv Clingen-Gene-Disease-Summary-2021-12-01.tsv \\
--uga Cache --out SupplementaryDatabase
---------------------------------------------------------------------------
SAUtils                                             (c) 2023 Illumina, Inc.
Stromberg, Roy, Platzer, Siddiqui, Ouyang, et al         3.21.0-0-gd2a0e953
---------------------------------------------------------------------------

Number of geneIds missing from the cache:0 (0%)

Time: 00:00:00.2

You can also use SAUtils command's subcommands AutoDownloadGenerate to generate ClinGen files. To use AutoDownloadGenerate, read more in SAUtils section.

Overview​

Publication

ISCA Regions​

TSV Extraction​

Status levels​

Parsing​

Conflict Resolution​

Clinical significance priority​

Validation Priority​

Download URL​

JSON Output​

Dosage Sensitivity Map​

Publication

TSV Source files​

Dosage Rating System​

Download URL​

JSON Output​

Building the supplementary files​

Gene-Disease Validity​

Publication

Source TSV​

Download URL​

Conflict Resolution​

Multiple Classifications​

Multiple Dates​

JSON Output​

Building the supplementary files​

Overview

ISCA Regions

TSV Extraction

Status levels

Parsing

Conflict Resolution

Clinical significance priority

Validation Priority

Download URL

JSON Output

Dosage Sensitivity Map

TSV Source files

Dosage Rating System

Download URL

JSON Output

Building the supplementary files

Gene-Disease Validity

Source TSV

Download URL

Conflict Resolution

Multiple Classifications

Multiple Dates

JSON Output

Building the supplementary files