1-40303912-T-C

Variant names:

• chr1-40303912-T-C
• rs6684531
• NM_001852.4:c.1368+16A>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.1368+16A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0299 in 1,551,628 control chromosomes in the GnomAD database, including 1,730 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.068 (668 hom., cov: 32)
  • Exomes 𝑓: 0.026 (1062 hom.)
• Consequence: COL9A2 NM_001852.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -4.33
• Publications: 1 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=-0.95).
• BP6: Variant 1-40303912-T-C is Benign according to our data. Variant chr1-40303912-T-C is described in ClinVar as Benign. ClinVar VariationId is 258374.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.174 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL9A2	NM_001852.4	c.1368+16A>G		intron_variant	Intron 26 of 31	ENST00000372748.8	NP_001843.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL9A2	ENST00000372748.8	c.1368+16A>G		intron_variant	Intron 26 of 31	1	NM_001852.4	ENSP00000361834.3
COL9A2	ENST00000482722.5	n.1671+16A>G		intron_variant	Intron 25 of 30	1
COL9A2	ENST00000427563.1	n.179+16A>G		intron_variant	Intron 4 of 6	3
COL9A2	ENST00000466267.1	n.333+16A>G		intron_variant	Intron 6 of 10	5

Frequencies

GnomAD3 genomes AF: 0.0673 AC: 10223 AN: 151878 Hom.: 660 Cov.: 32

Gnomad AFR AF: 0.177

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0428

Gnomad ASJ AF: 0.0406

Gnomad EAS AF: 0.0259

Gnomad SAS AF: 0.0340

Gnomad FIN AF: 0.0230

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0216

Gnomad OTH AF: 0.0446

GnomAD2 exomes AF: 0.0389 AC: 5724 AN: 147276 AF XY: 0.0366

Gnomad AFR exome AF: 0.181

Gnomad AMR exome AF: 0.0587

Gnomad ASJ exome AF: 0.0392

Gnomad EAS exome AF: 0.0220

Gnomad FIN exome AF: 0.0251

Gnomad NFE exome AF: 0.0202

Gnomad OTH exome AF: 0.0273

GnomAD4 exome AF: 0.0258 AC: 36170 AN: 1399634 Hom.: 1062 Cov.: 34 AF XY: 0.0259 AC XY: 17882 AN XY: 690494

African (AFR) AF: 0.190 AC: 6049 AN: 31778

American (AMR) AF: 0.0557 AC: 1993 AN: 35804

Ashkenazi Jewish (ASJ) AF: 0.0407 AC: 1023 AN: 25154

East Asian (EAS) AF: 0.0338 AC: 1216 AN: 36012

South Asian (SAS) AF: 0.0355 AC: 2820 AN: 79354

European-Finnish (FIN) AF: 0.0253 AC: 1230 AN: 48646

Middle Eastern (MID) AF: 0.0252 AC: 137 AN: 5438

European-Non Finnish (NFE) AF: 0.0183 AC: 19768 AN: 1079472

Other (OTH) AF: 0.0334 AC: 1934 AN: 57976

GnomAD4 genome AF: 0.0675 AC: 10262 AN: 151994 Hom.: 668 Cov.: 32 AF XY: 0.0675 AC XY: 5019 AN XY: 74308

African (AFR) AF: 0.178 AC: 7355 AN: 41428

American (AMR) AF: 0.0427 AC: 654 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0406 AC: 141 AN: 3472

East Asian (EAS) AF: 0.0259 AC: 133 AN: 5130

South Asian (SAS) AF: 0.0338 AC: 163 AN: 4824

European-Finnish (FIN) AF: 0.0230 AC: 244 AN: 10604

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0216 AC: 1464 AN: 67924

Other (OTH) AF: 0.0475 AC: 100 AN: 2106

Alfa AF: 0.0507 Hom.: 64

Bravo AF: 0.0735

Asia WGS AF: 0.0680 AC: 234 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

-

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 10, 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. -

Apr 29, 2016

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.42
DANN	Benign	0.39
PhyloP100		-4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs6684531; hg19: chr1-40769584;