rs1979785

Variant names:

• chr1-40312128-T-C
• rs1979785
• ENST00000482722.5:n.651A>G

Your query was ambiguous. Multiple possible variants found:

• chr1-40312128-T-C
• chr1-40312128-T-G

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The ENST00000482722.5(COL9A2):​n.651A>G variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000494 in 1,595,702 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00052 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00049 (0 hom.)
• Consequence: COL9A2 ENST00000482722.5 non_coding_transcript_exon
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: -0.550
• Publications: 14 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 1-40312128-T-C is Benign according to our data. Variant chr1-40312128-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 445655.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000515 (78/151430) while in subpopulation NFE AF = 0.000928 (63/67876). AF 95% confidence interval is 0.000744. There are 0 homozygotes in GnomAd4. There are 43 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL9A2	NM_001852.4	c.364-16A>G		intron_variant	Intron 7 of 31	ENST00000372748.8	NP_001843.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL9A2	ENST00000372748.8	c.364-16A>G		intron_variant	Intron 7 of 31	1	NM_001852.4	ENSP00000361834.3

Frequencies

GnomAD3 genomes AF: 0.000515 AC: 78 AN: 151430 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000122

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000394

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000953

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000928

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.000507 AC: 112 AN: 220972 AF XY: 0.000531

Gnomad AFR exome AF: 0.000142

Gnomad AMR exome AF: 0.000169

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000264

Gnomad NFE exome AF: 0.000982

Gnomad OTH exome AF: 0.000183

GnomAD4 exome AF: 0.000492 AC: 711 AN: 1444272 Hom.: 0 Cov.: 33 AF XY: 0.000515 AC XY: 369 AN XY: 716720

African (AFR) AF: 0.0000900 AC: 3 AN: 33346

American (AMR) AF: 0.000198 AC: 8 AN: 40414

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25624

East Asian (EAS) AF: 0.00 AC: 0 AN: 39086

South Asian (SAS) AF: 0.00 AC: 0 AN: 82728

European-Finnish (FIN) AF: 0.000191 AC: 10 AN: 52470

Middle Eastern (MID) AF: 0.000175 AC: 1 AN: 5714

European-Non Finnish (NFE) AF: 0.000607 AC: 671 AN: 1105034

Other (OTH) AF: 0.000301 AC: 18 AN: 59856

GnomAD4 genome AF: 0.000515 AC: 78 AN: 151430 Hom.: 0 Cov.: 31 AF XY: 0.000582 AC XY: 43 AN XY: 73892

African (AFR) AF: 0.000122 AC: 5 AN: 41118

American (AMR) AF: 0.000394 AC: 6 AN: 15232

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5146

South Asian (SAS) AF: 0.00 AC: 0 AN: 4794

European-Finnish (FIN) AF: 0.0000953 AC: 1 AN: 10494

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.000928 AC: 63 AN: 67876

Other (OTH) AF: 0.00144 AC: 3 AN: 2078

Alfa AF: 0.000135 Hom.: 410

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Jun 26, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 28, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:2

Oct 25, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: COL9A2 c.364-16A>G alters a nucleotide located at a position not widely known to affect splicing. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00051 in 220972 control chromosomes. To our knowledge, no occurrence of c.364-16A>G in individuals affected with Epiphyseal dysplasia, multiple, 2 and no experimental evidence demonstrating its impact on protein function have been reported. Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely benign. -

Sep 29, 2017

GeneDx

Significance: Likely 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. -

COL9A2-related disorder Benign:1

Dec 20, 2023

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	1.1
DANN	Benign	0.50
PhyloP100		-0.55
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs1979785; hg19: chr1-40777800;