rs121912873

Positions:

• chr12-47977626-CA-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001844.5(COL2A1):​c.3138del​(p.Gly1047AlafsTer83) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: COL2A1 NM_001844.5 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: -0.725

Genes affected

COL2A1 (HGNC:2200): (collagen type II alpha 1 chain) This gene encodes the alpha-1 chain of type II collagen, a fibrillar collagen found in cartilage and the vitreous humor of the eye. Mutations in this gene are associated with achondrogenesis, chondrodysplasia, early onset familial osteoarthritis, SED congenita, Langer-Saldino achondrogenesis, Kniest dysplasia, Stickler syndrome type I, and spondyloepimetaphyseal dysplasia Strudwick type. In addition, defects in processing chondrocalcin, a calcium binding protein that is the C-propeptide of this collagen molecule, are also associated with chondrodysplasia. There are two transcripts identified for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 12-47977626-CA-C is Pathogenic according to our data. Variant chr12-47977626-CA-C is described in ClinVar as [Pathogenic]. Clinvar id is 17365.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-47977626-CA-C is described in Lovd as [Pathogenic]. Variant chr12-47977626-CA-C is described in Lovd as [Pathogenic]. Variant chr12-47977626-CA-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL2A1	NM_001844.5	c.3138del	p.Gly1047AlafsTer83	frameshift_variant	45/54	ENST00000380518.8	NP_001835.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL2A1	ENST00000380518.8	c.3138del	p.Gly1047AlafsTer83	frameshift_variant	45/54	1	NM_001844.5	ENSP00000369889	P1
COL2A1	ENST00000337299.7	c.2931del	p.Gly978AlafsTer83	frameshift_variant	44/53	1		ENSP00000338213
COL2A1	ENST00000493991.5	n.2224del		non_coding_transcript_exon_variant	28/37	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 28, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Apr 07, 2023	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 17365). This variant is also known as c.2931delT (p.P977fs). This premature translational stop signal has been observed in individual(s) with COL2A1-related conditions (PMID: 8406454, 20513134, 31872526). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gly1047Alafs*83) in the COL2A1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in COL2A1 are known to be pathogenic (PMID: 20179744). -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 13, 2023	Not observed at significant frequency in large population cohorts (gnomAD); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 29453956, 31872526, 30181686, 20179744, 8406454) -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 16, 2018	The COL2A1 c.3138delT; p.Gly1047fs variant (rs121912873) has been described in individuals with Stickler syndrome (Hoornaert 2010, Richards 2010). It is reported as pathogenic in ClinVar (Variation ID: 17365) and is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. This variant creates a frameshift by deleting a single nucleotide, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered pathogenic. References: Hoornaert K et al. Stickler syndrome caused by COL2A1 mutations: genotype-phenotype correlation in a series of 100 patients. Eur J Hum Genet. 2010 Aug;18(8):872-80. Richards A et al. Stickler syndrome and the vitreous phenotype: mutations in COL2A1 and COL11A1. Hum Mutat. 2010 Jun;31(6):E1461-71. -

Stickler syndrome type 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 01, 1993

- -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs121912873; hg19: chr12-48371409;