rs3737815

Variant names:

• chr1-40311080-C-A
• rs3737815
• NM_001852.4:c.630+13G>T

Your query was ambiguous. Multiple possible variants found:

• chr1-40311080-C-A
• chr1-40311080-C-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001852.4(COL9A2):​c.630+13G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.165 in 1,613,654 control chromosomes in the GnomAD database, including 24,982 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (1917 hom., cov: 32)
  • Exomes 𝑓: 0.17 (23065 hom.)
• Consequence: COL9A2 NM_001852.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.0370
• Publications: 12 publications found

Genes affected

COL9A2 (HGNC:2218): (collagen type IX alpha 2 chain) This gene encodes one of the three alpha chains of type IX collagen, the major collagen component of hyaline cartilage. Type IX collagen, a heterotrimeric molecule, is usually found in tissues containing type II collagen, a fibrillar collagen. This chain is unusual in that, unlike the other two type IX alpha chains, it contains a covalently attached glycosaminoglycan side chain. Mutations in this gene are associated with multiple epiphyseal dysplasia. [provided by RefSeq, Jul 2008]

COL9A2 Gene-Disease associations (from GenCC):

• epiphyseal dysplasia, multiple, 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• Stickler syndrome, type 5

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp
• multiple epiphyseal dysplasia due to collagen 9 anomaly

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• autosomal recessive Stickler syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Stickler syndrome

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 1-40311080-C-A is Benign according to our data. Variant chr1-40311080-C-A is described in CliVar as Benign. Clinvar id is 258392.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-40311080-C-A is described in CliVar as Benign. Clinvar id is 258392.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-40311080-C-A is described in CliVar as Benign. Clinvar id is 258392.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-40311080-C-A is described in CliVar as Benign. Clinvar id is 258392.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-40311080-C-A is described in CliVar as Benign. Clinvar id is 258392.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-40311080-C-A is described in CliVar as Benign. Clinvar id is 258392.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-40311080-C-A is described in CliVar as Benign. Clinvar id is 258392.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-40311080-C-A is described in CliVar as Benign. Clinvar id is 258392.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.398 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL9A2	NM_001852.4	c.630+13G>T		intron_variant	Intron 12 of 31	ENST00000372748.8	NP_001843.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL9A2	ENST00000372748.8	c.630+13G>T		intron_variant	Intron 12 of 31	1	NM_001852.4	ENSP00000361834.3
COL9A2	ENST00000482722.5	n.933+13G>T		intron_variant	Intron 11 of 30	1
COL9A2	ENST00000417105.6	c.348+13G>T		intron_variant	Intron 12 of 13	5		ENSP00000388493.2
COL9A2	ENST00000488463.6	n.681+13G>T		intron_variant	Intron 11 of 13	5

Frequencies

GnomAD3 genomes AF: 0.140 AC: 21272 AN: 152082 Hom.: 1915 Cov.: 32

Gnomad AFR AF: 0.0532

Gnomad AMI AF: 0.191

Gnomad AMR AF: 0.201

Gnomad ASJ AF: 0.135

Gnomad EAS AF: 0.412

Gnomad SAS AF: 0.0977

Gnomad FIN AF: 0.178

Gnomad MID AF: 0.0823

Gnomad NFE AF: 0.156

Gnomad OTH AF: 0.122

GnomAD2 exomes AF: 0.174 AC: 43816 AN: 251264 AF XY: 0.168

Gnomad AFR exome AF: 0.0548

Gnomad AMR exome AF: 0.248

Gnomad ASJ exome AF: 0.132

Gnomad EAS exome AF: 0.385

Gnomad FIN exome AF: 0.184

Gnomad NFE exome AF: 0.159

Gnomad OTH exome AF: 0.160

GnomAD4 exome AF: 0.168 AC: 245050 AN: 1461454 Hom.: 23065 Cov.: 37 AF XY: 0.166 AC XY: 120408 AN XY: 727042

African (AFR) AF: 0.0497 AC: 1662 AN: 33468

American (AMR) AF: 0.243 AC: 10857 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.137 AC: 3583 AN: 26132

East Asian (EAS) AF: 0.431 AC: 17091 AN: 39698

South Asian (SAS) AF: 0.0987 AC: 8508 AN: 86244

European-Finnish (FIN) AF: 0.187 AC: 9969 AN: 53418

Middle Eastern (MID) AF: 0.0818 AC: 456 AN: 5576

European-Non Finnish (NFE) AF: 0.165 AC: 183126 AN: 1111832

Other (OTH) AF: 0.162 AC: 9798 AN: 60366

GnomAD4 genome AF: 0.140 AC: 21274 AN: 152200 Hom.: 1917 Cov.: 32 AF XY: 0.141 AC XY: 10462 AN XY: 74404

African (AFR) AF: 0.0532 AC: 2209 AN: 41552

American (AMR) AF: 0.201 AC: 3074 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.135 AC: 470 AN: 3470

East Asian (EAS) AF: 0.412 AC: 2125 AN: 5152

South Asian (SAS) AF: 0.0971 AC: 468 AN: 4818

European-Finnish (FIN) AF: 0.178 AC: 1882 AN: 10602

Middle Eastern (MID) AF: 0.0884 AC: 26 AN: 294

European-Non Finnish (NFE) AF: 0.156 AC: 10591 AN: 67986

Other (OTH) AF: 0.121 AC: 255 AN: 2114

Alfa AF: 0.136 Hom.: 955

Bravo AF: 0.141

Asia WGS AF: 0.228 AC: 793 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 30, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Epiphyseal dysplasia, multiple, 2 Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	7.7
DANN	Benign	0.86
PhyloP100		-0.037
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.17		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs3737815; hg19: chr1-40776752; COSMIC: COSV65607609; COSMIC: COSV65607609;