rs56326652

Variant names:

• chr1-40310254-A-G
• rs56326652
• NM_001852.4:c.738+10T>C

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.738+10T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0533 in 1,613,950 control chromosomes in the GnomAD database, including 2,581 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.043 (217 hom., cov: 32)
  • Exomes 𝑓: 0.054 (2364 hom.)
• Consequence: COL9A2 NM_001852.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.267
• Publications: 3 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=-0.84).
• BP6: Variant 1-40310254-A-G is Benign according to our data. Variant chr1-40310254-A-G is described in ClinVar as [Benign]. Clinvar id is 258394.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0631 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL9A2	NM_001852.4	c.738+10T>C		intron_variant	Intron 14 of 31	ENST00000372748.8	NP_001843.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL9A2	ENST00000372748.8	c.738+10T>C		intron_variant	Intron 14 of 31	1	NM_001852.4	ENSP00000361834.3
COL9A2	ENST00000482722.5	n.1041+10T>C		intron_variant	Intron 13 of 30	1
COL9A2	ENST00000488463.6	n.789+10T>C		intron_variant	Intron 13 of 13	5
COL9A2	ENST00000417105.6	c.*36T>C		downstream_gene_variant		5		ENSP00000388493.2

Frequencies

GnomAD3 genomes AF: 0.0426 AC: 6481 AN: 152114 Hom.: 217 Cov.: 32

Gnomad AFR AF: 0.0101

Gnomad AMI AF: 0.00659

Gnomad AMR AF: 0.0290

Gnomad ASJ AF: 0.0470

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0298

Gnomad FIN AF: 0.0772

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0647

Gnomad OTH AF: 0.0392

GnomAD2 exomes AF: 0.0444 AC: 11170 AN: 251408 AF XY: 0.0458

Gnomad AFR exome AF: 0.0100

Gnomad AMR exome AF: 0.0213

Gnomad ASJ exome AF: 0.0442

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0710

Gnomad NFE exome AF: 0.0625

Gnomad OTH exome AF: 0.0459

GnomAD4 exome AF: 0.0544 AC: 79587 AN: 1461718 Hom.: 2364 Cov.: 34 AF XY: 0.0542 AC XY: 39403 AN XY: 727172

African (AFR) AF: 0.00848 AC: 284 AN: 33478

American (AMR) AF: 0.0227 AC: 1017 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0468 AC: 1223 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.0298 AC: 2571 AN: 86258

European-Finnish (FIN) AF: 0.0660 AC: 3522 AN: 53398

Middle Eastern (MID) AF: 0.0293 AC: 169 AN: 5768

European-Non Finnish (NFE) AF: 0.0611 AC: 67939 AN: 1111864

Other (OTH) AF: 0.0474 AC: 2861 AN: 60394

GnomAD4 genome AF: 0.0426 AC: 6480 AN: 152232 Hom.: 217 Cov.: 32 AF XY: 0.0429 AC XY: 3191 AN XY: 74424

African (AFR) AF: 0.0100 AC: 417 AN: 41524

American (AMR) AF: 0.0290 AC: 443 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0470 AC: 163 AN: 3470

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5188

South Asian (SAS) AF: 0.0303 AC: 146 AN: 4826

European-Finnish (FIN) AF: 0.0772 AC: 818 AN: 10602

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0647 AC: 4401 AN: 68004

Other (OTH) AF: 0.0388 AC: 82 AN: 2114

Alfa AF: 0.0486 Hom.: 71

Bravo AF: 0.0365

Asia WGS AF: 0.0130 AC: 46 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

-

Genome Diagnostics Laboratory, Amsterdam University Medical Center

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

- -

-

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 17, 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

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Epiphyseal dysplasia, multiple, 2 Benign:1

Jan 13, 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. -

Connective tissue disorder Benign:1

May 12, 2022

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	5.4
DANN	Benign	0.64
PhyloP100		-0.27
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs56326652; hg19: chr1-40775926;