rs387906609

Positions:

• chr21-46117916-C-T
• chr21-46117916-C-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_001849.4(COL6A2):​c.1096C>T​(p.Arg366Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000144 in 1,460,628 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: COL6A2 NM_001849.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 2.24

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 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 21-46117916-C-T is Pathogenic according to our data. Variant chr21-46117916-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 29643.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46117916-C-T is described in Lovd as [Pathogenic]. Variant chr21-46117916-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL6A2	NM_001849.4	c.1096C>T	p.Arg366Ter	stop_gained	12/28	ENST00000300527.9	NP_001840.3
COL6A2	NM_058174.3	c.1096C>T	p.Arg366Ter	stop_gained	12/28	ENST00000397763.6	NP_478054.2
COL6A2	NM_058175.3	c.1096C>T	p.Arg366Ter	stop_gained	12/28		NP_478055.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL6A2	ENST00000300527.9	c.1096C>T	p.Arg366Ter	stop_gained	12/28	1	NM_001849.4	ENSP00000300527	P1
COL6A2	ENST00000397763.6	c.1096C>T	p.Arg366Ter	stop_gained	12/28	5	NM_058174.3	ENSP00000380870
COL6A2	ENST00000409416.6	c.1096C>T	p.Arg366Ter	stop_gained	11/27	5		ENSP00000387115

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000403 AC: 1 AN: 248010 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 134572

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.00000894

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000144 AC: 21 AN: 1460628 Hom.: 0 Cov.: 32 AF XY: 0.0000124 AC XY: 9 AN XY: 726574

Gnomad4 AFR exome AF: 0.0000299

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: 0.0000162

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000620 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 29, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 25, 2024	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); This variant is associated with the following publications: (PMID: 19309692, 31471117, 27375477, 24801232, Hu2024[Casereport], 29419890, 37569848, 19949035) -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 03, 2022	- -

Bethlem myopathy 1A Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 12, 2024	This sequence change creates a premature translational stop signal (p.Arg366*) 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). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individuals with autosomal recessive COL6A2-related muscular dystrophy (PMID: 19309692, 19949035, 24801232, 29419890). ClinVar contains an entry for this variant (Variation ID: 29643). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

BETHLEM MYOPATHY 1B, AUTOSOMAL RECESSIVE Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 01, 2009

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	39
DANN	Uncertain	1.0
Eigen	Benign	0.17
Eigen_PC	Benign	-0.053
FATHMM_MKL	Uncertain	0.96	D
MutationTaster	Benign	1.0	A;A;A;A;A
Vest4		0.84
GERP RS		3.6

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs387906609; hg19: chr21-47537830; COSMIC: COSV100153522; COSMIC: COSV100153522;