rs112370406

Variant names:

• chr1-40303916-C-T
• rs112370406
• NM_001852.4:c.1368+12G>A

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+12G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0608 in 1,552,050 control chromosomes in the GnomAD database, including 3,085 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.051 (224 hom., cov: 32)
  • Exomes 𝑓: 0.062 (2861 hom.)
• Consequence: COL9A2 NM_001852.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.04
• Publications: 2 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=-0.87).
• BP6: Variant 1-40303916-C-T is Benign according to our data. Variant chr1-40303916-C-T is described in ClinVar as Benign. ClinVar VariationId is 258373.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0608 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL9A2	NM_001852.4	c.1368+12G>A		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+12G>A		intron_variant	Intron 26 of 31	1	NM_001852.4	ENSP00000361834.3
COL9A2	ENST00000482722.5	n.1671+12G>A		intron_variant	Intron 25 of 30	1
COL9A2	ENST00000427563.1	n.179+12G>A		intron_variant	Intron 4 of 6	3
COL9A2	ENST00000466267.1	n.333+12G>A		intron_variant	Intron 6 of 10	5

Frequencies

GnomAD3 genomes AF: 0.0514 AC: 7823 AN: 152092 Hom.: 224 Cov.: 32

Gnomad AFR AF: 0.0379

Gnomad AMI AF: 0.0384

Gnomad AMR AF: 0.0553

Gnomad ASJ AF: 0.0821

Gnomad EAS AF: 0.00406

Gnomad SAS AF: 0.0370

Gnomad FIN AF: 0.0468

Gnomad MID AF: 0.0601

Gnomad NFE AF: 0.0624

Gnomad OTH AF: 0.0622

GnomAD2 exomes AF: 0.0538 AC: 7952 AN: 147756 AF XY: 0.0539

Gnomad AFR exome AF: 0.0381

Gnomad AMR exome AF: 0.0595

Gnomad ASJ exome AF: 0.0824

Gnomad EAS exome AF: 0.00260

Gnomad FIN exome AF: 0.0524

Gnomad NFE exome AF: 0.0641

Gnomad OTH exome AF: 0.0584

GnomAD4 exome AF: 0.0619 AC: 86616 AN: 1399840 Hom.: 2861 Cov.: 34 AF XY: 0.0615 AC XY: 42469 AN XY: 690618

African (AFR) AF: 0.0358 AC: 1138 AN: 31804

American (AMR) AF: 0.0561 AC: 2009 AN: 35828

Ashkenazi Jewish (ASJ) AF: 0.0804 AC: 2023 AN: 25156

East Asian (EAS) AF: 0.00602 AC: 217 AN: 36050

South Asian (SAS) AF: 0.0433 AC: 3433 AN: 79358

European-Finnish (FIN) AF: 0.0506 AC: 2462 AN: 48650

Middle Eastern (MID) AF: 0.0516 AC: 281 AN: 5448

European-Non Finnish (NFE) AF: 0.0664 AC: 71681 AN: 1079562

Other (OTH) AF: 0.0582 AC: 3372 AN: 57984

GnomAD4 genome AF: 0.0514 AC: 7816 AN: 152210 Hom.: 224 Cov.: 32 AF XY: 0.0499 AC XY: 3710 AN XY: 74412

African (AFR) AF: 0.0377 AC: 1566 AN: 41534

American (AMR) AF: 0.0552 AC: 845 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0821 AC: 285 AN: 3472

East Asian (EAS) AF: 0.00426 AC: 22 AN: 5166

South Asian (SAS) AF: 0.0368 AC: 178 AN: 4832

European-Finnish (FIN) AF: 0.0468 AC: 497 AN: 10612

Middle Eastern (MID) AF: 0.0646 AC: 19 AN: 294

European-Non Finnish (NFE) AF: 0.0624 AC: 4241 AN: 67972

Other (OTH) AF: 0.0606 AC: 128 AN: 2112

Alfa AF: 0.0591 Hom.: 56

Bravo AF: 0.0515

Asia WGS AF: 0.0210 AC: 72 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 05, 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	-0.87
CADD	Benign	3.5
DANN	Benign	0.93
PhyloP100		-1.0
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: rs112370406; hg19: chr1-40769588;