chr2-237344422-C-T

Position:

• chr2-237344422-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_004369.4(COL6A3):​c.7596G>A​(p.Lys2532=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.122 in 1,614,090 control chromosomes in the GnomAD database, including 12,659 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1390 hom., cov: 32)
  • Exomes 𝑓: 0.12 (11269 hom.)
• Consequence: COL6A3 NM_004369.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 1.19

Genes affected

COL6A3 (HGNC:2213): (collagen type VI alpha 3 chain) This gene encodes the alpha-3 chain, one of the three alpha chains of type VI collagen, a beaded filament collagen found in most connective tissues. The alpha-3 chain of type VI collagen is much larger than the alpha-1 and -2 chains. This difference in size is largely due to an increase in the number of subdomains, similar to von Willebrand Factor type A domains, that are found in the amino terminal globular domain of all the alpha chains. 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 the type VI collagen genes are associated with Bethlem myopathy, a rare autosomal dominant proximal myopathy with early childhood onset. Mutations in this gene are also a cause of Ullrich congenital muscular dystrophy, also referred to as Ullrich scleroatonic muscular dystrophy, an autosomal recessive congenital myopathy that is more severe than Bethlem myopathy. Multiple transcript variants have been identified, but the full-length nature of only some of these variants has been described. [provided by RefSeq, Jun 2009]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.35).
• BP6: Variant 2-237344422-C-T is Benign according to our data. Variant chr2-237344422-C-T is described in ClinVar as [Benign]. Clinvar id is 94990.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-237344422-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=1.19 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.173 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL6A3	NM_004369.4	c.7596G>A	p.Lys2532=	synonymous_variant	36/44	ENST00000295550.9
COL6A3	NM_057167.4	c.6978G>A	p.Lys2326=	synonymous_variant	35/43
COL6A3	NM_057166.5	c.5775G>A	p.Lys1925=	synonymous_variant	33/41

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL6A3	ENST00000295550.9	c.7596G>A	p.Lys2532=	synonymous_variant	36/44	1	NM_004369.4	P1

Frequencies

GnomAD3 genomes AF: 0.131 AC: 19866 AN: 152092 Hom.: 1377 Cov.: 32

Gnomad AFR AF: 0.170

Gnomad AMI AF: 0.0921

Gnomad AMR AF: 0.121

Gnomad ASJ AF: 0.123

Gnomad EAS AF: 0.183

Gnomad SAS AF: 0.178

Gnomad FIN AF: 0.0846

Gnomad MID AF: 0.0823

Gnomad NFE AF: 0.110

Gnomad OTH AF: 0.116

GnomAD3 exomes AF: 0.128 AC: 32192 AN: 251394 Hom.: 2240 AF XY: 0.128 AC XY: 17351 AN XY: 135860

Gnomad AFR exome AF: 0.169

Gnomad AMR exome AF: 0.128

Gnomad ASJ exome AF: 0.130

Gnomad EAS exome AF: 0.174

Gnomad SAS exome AF: 0.178

Gnomad FIN exome AF: 0.0863

Gnomad NFE exome AF: 0.110

Gnomad OTH exome AF: 0.118

GnomAD4 exome AF: 0.121 AC: 176814 AN: 1461880 Hom.: 11269 Cov.: 33 AF XY: 0.122 AC XY: 88755 AN XY: 727242

Gnomad4 AFR exome AF: 0.170

Gnomad4 AMR exome AF: 0.129

Gnomad4 ASJ exome AF: 0.120

Gnomad4 EAS exome AF: 0.164

Gnomad4 SAS exome AF: 0.178

Gnomad4 FIN exome AF: 0.0894

Gnomad4 NFE exome AF: 0.114

Gnomad4 OTH exome AF: 0.138

GnomAD4 genome AF: 0.131 AC: 19918 AN: 152210 Hom.: 1390 Cov.: 32 AF XY: 0.129 AC XY: 9574 AN XY: 74412

Gnomad4 AFR AF: 0.170

Gnomad4 AMR AF: 0.122

Gnomad4 ASJ AF: 0.123

Gnomad4 EAS AF: 0.183

Gnomad4 SAS AF: 0.179

Gnomad4 FIN AF: 0.0846

Gnomad4 NFE AF: 0.110

Gnomad4 OTH AF: 0.123

Alfa AF: 0.116 Hom.: 1546

Bravo AF: 0.137

Asia WGS AF: 0.196 AC: 683 AN: 3478

EpiCase AF: 0.115

EpiControl AF: 0.111

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 07, 2012	- -
Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jul 31, 2024	This variant is classified as Benign based on local population frequency. This variant was detected in 34% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy, Progressive Myoclonus Epilepsy and Abnormal Movements and Neurodegeneration with brain iron accumulation. Number of patients: 32. Only high quality variants are reported. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 25, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Ullrich congenital muscular dystrophy 1A;CN029274:Bethlem myopathy 1A Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Jun 19, 2017

- -

Collagen 6-related myopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Bethlem myopathy 1A Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.35
CADD	Benign	8.1
DANN	Benign	0.51

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: rs2291795; hg19: chr2-238253065; COSMIC: COSV55084005; COSMIC: COSV55084005;