rs1555166218

Positions:

• chr12-47981803-AG-A
• chr12-47981803-AG-AGG

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.2381del​(p.Pro794LeufsTer87) variant causes a frameshift change involving the alteration of a 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)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: COL2A1 NM_001844.5 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 9.89

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]

LOC105369752 (HGNC:):

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 12-47981803-AG-A is Pathogenic according to our data. Variant chr12-47981803-AG-A is described in ClinVar as [Pathogenic]. Clinvar id is 547258.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-47981803-AG-A is described in Lovd as [Pathogenic]. Variant chr12-47981803-AG-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL2A1	NM_001844.5	c.2381del	p.Pro794LeufsTer87	frameshift_variant	36/54	ENST00000380518.8	NP_001835.3
LOC105369752	XR_944910.2	n.218+383del		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL2A1	ENST00000380518.8	c.2381del	p.Pro794LeufsTer87	frameshift_variant	36/54	1	NM_001844.5	ENSP00000369889	P1
COL2A1	ENST00000337299.7	c.2174del	p.Pro725LeufsTer87	frameshift_variant	35/53	1		ENSP00000338213
COL2A1	ENST00000483376.1	n.559del		non_coding_transcript_exon_variant	7/8	5
COL2A1	ENST00000493991.5	n.1467del		non_coding_transcript_exon_variant	19/37	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1402270 Hom.: 0 Cov.: 36 AF XY: 0.00 AC XY: 0 AN XY: 692042

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 22, 2021	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 547258). This variant is also known as deletion of nt 22,620 (C) in E34. This premature translational stop signal has been observed in individual(s) with Stickler syndrome (PMID: 10486316). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Pro794Leufs*87) 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	Clinical Genetics and Genomics, Karolinska University Hospital	Sep 06, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 10, 2022	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; Not observed at significant frequency in large population cohorts (gnomAD); Reported in ClinVar as a pathogenic variant but additional evidence is not available (ClinVar Variant ID# 547258; ClinVar); This variant is associated with the following publications: (PMID: 10486316, 33726816) -

Stickler syndrome type 1 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	3billion	Jan 03, 2022	Frameshift: predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant (PVS1_VS). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000547258, PMID:10486316). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Human Genetics, Inc, Center for Human Genetics, Inc	Nov 01, 2016	- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1555166218; hg19: chr12-48375586;