chr12-48000055-G-T

Position:

• chr12-48000055-G-T

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.156C>A​(p.Cys52*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: COL2A1 NM_001844.5 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 3.45

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]

COL2A1 (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 12-48000055-G-T is Pathogenic according to our data. Variant chr12-48000055-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 547245.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL2A1	NM_001844.5	c.156C>A	p.Cys52*	stop_gained	2/54	ENST00000380518.8	NP_001835.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL2A1	ENST00000380518.8	c.156C>A	p.Cys52*	stop_gained	2/54	1	NM_001844.5	ENSP00000369889.3
COL2A1	ENST00000337299.7	c.86-1624C>A		intron_variant		1		ENSP00000338213.6
COL2A1	ENST00000474996.6	n.394C>A		non_coding_transcript_exon_variant	3/8	3
COL2A1	ENST00000490609.2	n.389C>A		non_coding_transcript_exon_variant	2/2	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 10, 2023	Has not been previously published as pathogenic or benign to our knowledge; Nonsense 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) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 07, 2020	For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in COL2A1 are known to be pathogenic (PMID: 20179744). This variant has not been reported in the literature in individuals with COL2A1-related conditions. ClinVar contains an entry for this variant (Variation ID: 547245). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Cys52*) in the COL2A1 gene. It is expected to result in an absent or disrupted protein product. -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 14, 2024

The c.156C>A (p.C52*) alteration, located in exon 2 (coding exon 2) of the COL2A1 gene, consists of a C to A substitution at nucleotide position 156. This changes the amino acid from a cysteine (C) to a stop codon at amino acid position 52. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). Based on the available evidence, this alteration is classified as pathogenic. -

COL2A1-related disorder Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 26, 2024

The COL2A1 c.156C>A variant is predicted to result in premature protein termination (p.Cys52*). To our knowledge, this variant has not been reported in the literature or in a large population database, indicating this variant is rare. Nonsense variants in COL2A1 are expected to be pathogenic. This variant is interpreted as likely pathogenic. -

Stickler syndrome type 1 Pathogenic:1

Likely 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

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.61	D
BayesDel_noAF	Pathogenic	0.63
CADD	Pathogenic	38
DANN	Uncertain	0.99
Eigen	Pathogenic	0.79
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Uncertain	0.95	D
Vest4		0.94
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs1246771678; hg19: chr12-48393838; COSMIC: COSV61528499; COSMIC: COSV61528499;