rs1555873508

Positions:

• chr21-46117875-GC-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_001849.4(COL6A2):​c.1059delC​(p.Asp354fs) 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: COL6A2 NM_001849.4 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.0680

Genes affected

COL6A2 (HGNC:2212): (collagen type VI alpha 2 chain) This gene encodes one of the three alpha chains of type VI collagen, a beaded filament collagen found in most connective tissues. The product of this gene contains several domains similar to von Willebrand Factor type A domains. These domains have been shown to bind extracellular matrix proteins, an interaction that explains the importance of this collagen in organizing matrix components. Mutations in this gene are associated with Bethlem myopathy and Ullrich scleroatonic muscular dystrophy. Three transcript variants have been identified for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 12 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 21-46117875-GC-G is Pathogenic according to our data. Variant chr21-46117875-GC-G is described in ClinVar as [Pathogenic]. Clinvar id is 542957.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL6A2	NM_001849.4	c.1059delC	p.Asp354fs	frameshift_variant	12/28	ENST00000300527.9	NP_001840.3
COL6A2	NM_058174.3	c.1059delC	p.Asp354fs	frameshift_variant	12/28		NP_478054.2
COL6A2	NM_058175.3	c.1059delC	p.Asp354fs	frameshift_variant	12/28		NP_478055.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL6A2	ENST00000300527.9	c.1059delC	p.Asp354fs	frameshift_variant	12/28	1	NM_001849.4	ENSP00000300527.4
COL6A2	ENST00000397763.6	c.1059delC	p.Asp354fs	frameshift_variant	12/28	5		ENSP00000380870.1
COL6A2	ENST00000409416.6	c.1059delC	p.Asp354fs	frameshift_variant	11/27	5		ENSP00000387115.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Bethlem myopathy 1A Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 09, 2018

This variant has not been reported in the literature in individuals with COL6A2-related disease. This sequence change creates a premature translational stop signal (p.Asp354Thrfs*54) in the COL6A2 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). Loss-of-function variants in COL6A2 are known to be pathogenic (PMID: 19884007, 20976770). For these reasons, this variant has been classified as Pathogenic. -

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: rs1555873508; hg19: chr21-47537789;