rs1375040481

Positions:

• chr21-46112503-AACGAC-A

Variant summary

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

The ENST00000300527.9(COL6A2):​c.641_645del​(p.Asn214IlefsTer60) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,682 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. N214N) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: COL6A2 ENST00000300527.9 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 2.23

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 21-46112503-AACGAC-A is Pathogenic according to our data. Variant chr21-46112503-AACGAC-A is described in ClinVar as [Pathogenic]. Clinvar id is 542956.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr21-46112503-AACGAC-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL6A2	NM_001849.4	c.641_645del	p.Asn214IlefsTer60	frameshift_variant	3/28	ENST00000300527.9	NP_001840.3
COL6A2	NM_058174.3	c.641_645del	p.Asn214IlefsTer60	frameshift_variant	3/28	ENST00000397763.6	NP_478054.2
COL6A2	NM_058175.3	c.641_645del	p.Asn214IlefsTer60	frameshift_variant	3/28		NP_478055.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL6A2	ENST00000300527.9	c.641_645del	p.Asn214IlefsTer60	frameshift_variant	3/28	1	NM_001849.4	ENSP00000300527	P1
COL6A2	ENST00000397763.6	c.641_645del	p.Asn214IlefsTer60	frameshift_variant	3/28	5	NM_058174.3	ENSP00000380870
COL6A2	ENST00000409416.6	c.641_645del	p.Asn214IlefsTer60	frameshift_variant	2/27	5		ENSP00000387115
COL6A2	ENST00000460886.1	n.87_91del		non_coding_transcript_exon_variant	1/2	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000410 AC: 1 AN: 244106 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 133488

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459682 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 726204

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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.: 32

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

Sep 29, 2021

This sequence change creates a premature translational stop signal (p.Asn214Ilefs*60) in the COL6A2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in COL6A2 are known to be pathogenic (PMID: 19884007, 20976770). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 542956). This variant has not been reported in the literature in individuals affected with COL6A2-related conditions. This variant is not present in population databases (ExAC no frequency). -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1375040481; hg19: chr21-47532417;