21-46125817-G-T

Variant names:

• chr21-46125817-G-T
• rs138948335
• NM_001849.4:c.2002G>T

Variant summary

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

The NM_001849.4(COL6A2):​c.2002G>T​(p.Glu668*) variant causes a stop gained change involving the alteration of a 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 Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: COL6A2 NM_001849.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 7.47

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 21-46125817-G-T is Pathogenic according to our data. Variant chr21-46125817-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 476462.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL6A2	NM_001849.4	c.2002G>T	p.Glu668*	stop_gained	Exon 26 of 28	ENST00000300527.9	NP_001840.3
COL6A2	NM_058174.3	c.2002G>T	p.Glu668*	stop_gained	Exon 26 of 28		NP_478054.2
COL6A2	NM_058175.3	c.2002G>T	p.Glu668*	stop_gained	Exon 26 of 28		NP_478055.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL6A2	ENST00000300527.9	c.2002G>T	p.Glu668*	stop_gained	Exon 26 of 28	1	NM_001849.4	ENSP00000300527.4
COL6A2	ENST00000397763.6	c.2002G>T	p.Glu668*	stop_gained	Exon 26 of 28	5		ENSP00000380870.1
COL6A2	ENST00000409416.6	c.2002G>T	p.Glu668*	stop_gained	Exon 25 of 27	5		ENSP00000387115.1
COL6A2	ENST00000413758.1	c.673G>T	p.Glu225*	stop_gained	Exon 11 of 11	3		ENSP00000395751.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

Jan 06, 2025

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2002G>T (p.E668*) alteration, located in exon 26 (coding exon 25) of the COL6A2 gene, consists of a G to T substitution at nucleotide position 2002. This changes the amino acid from a glutamic acid (E) to a stop codon at amino acid position 668. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Although biallelic loss of function of COL6A2 has been associated with autosomal recessive COL6A2-related myopathy, haploinsufficiency of COL6A2 has not been established as a mechanism of disease for autosomal dominant COL6A2-related myopathy. for autosomal recessive COL6A2-related myopathy; however, its clinical significance for autosomal dominant COL6A2-related myopathy is uncertain. 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. -

Bethlem myopathy 1A Pathogenic:1

Nov 29, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 476462). This variant has not been reported in the literature in individuals affected with COL6A2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Glu668*) 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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	56
DANN	Uncertain	1.0
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Uncertain	0.95	D
Vest4		0.81
GERP RS		4.4

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs138948335; hg19: chr21-47545731;