rs2646254

chr2-237359074-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_004369.4(COL6A3):c.6369G>A(p.Leu2123=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.173 in 1,612,952 control chromosomes in the GnomAD database, including 30,488 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.25 (6552 hom., cov: 33)
  • Exomes 𝑓: 0.16 (23936 hom.)
• Consequence: COL6A3 NM_004369.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -0.0350

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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.31).
• BP6: Variant 2-237359074-C-T is Benign according to our data. Variant chr2-237359074-C-T is described in ClinVar as [Benign]. Clinvar id is 94962.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-237359074-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.463 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL6A3	NM_004369.4	c.6369G>A	p.Leu2123=	synonymous_variant	20/44	ENST00000295550.9
COL6A3	NM_057167.4	c.5751G>A	p.Leu1917=	synonymous_variant	19/43
COL6A3	NM_057166.5	c.4548G>A	p.Leu1516=	synonymous_variant	17/41

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL6A3	ENST00000295550.9	c.6369G>A	p.Leu2123=	synonymous_variant	20/44	1	NM_004369.4	P1
COL6A3	ENST00000472056.5	c.4548G>A	p.Leu1516=	synonymous_variant	17/41	1
COL6A3	ENST00000353578.9	c.5751G>A	p.Leu1917=	synonymous_variant	19/43	5

Frequencies

GnomAD3 genomes AF: 0.253 AC: 38527 AN: 152028 Hom.: 6518 Cov.: 33

Gnomad AFR AF: 0.468

Gnomad AMI AF: 0.139

Gnomad AMR AF: 0.277

Gnomad ASJ AF: 0.172

Gnomad EAS AF: 0.355

Gnomad SAS AF: 0.261

Gnomad FIN AF: 0.121

Gnomad MID AF: 0.253

Gnomad NFE AF: 0.136

Gnomad OTH AF: 0.244

GnomAD3 exomes AF: 0.213 AC: 53684 AN: 251486 Hom.: 7147 AF XY: 0.206 AC XY: 27961 AN XY: 135918

Gnomad AFR exome AF: 0.487

Gnomad AMR exome AF: 0.289

Gnomad ASJ exome AF: 0.170

Gnomad EAS exome AF: 0.360

Gnomad SAS exome AF: 0.253

Gnomad FIN exome AF: 0.127

Gnomad NFE exome AF: 0.139

Gnomad OTH exome AF: 0.179

GnomAD4 exome AF: 0.165 AC: 240631 AN: 1460806 Hom.: 23936 Cov.: 35 AF XY: 0.166 AC XY: 120329 AN XY: 726750

Gnomad4 AFR exome AF: 0.489

Gnomad4 AMR exome AF: 0.288

Gnomad4 ASJ exome AF: 0.163

Gnomad4 EAS exome AF: 0.335

Gnomad4 SAS exome AF: 0.251

Gnomad4 FIN exome AF: 0.124

Gnomad4 NFE exome AF: 0.138

Gnomad4 OTH exome AF: 0.187

GnomAD4 genome AF: 0.254 AC: 38623 AN: 152146 Hom.: 6552 Cov.: 33 AF XY: 0.256 AC XY: 19024 AN XY: 74396

Gnomad4 AFR AF: 0.468

Gnomad4 AMR AF: 0.278

Gnomad4 ASJ AF: 0.172

Gnomad4 EAS AF: 0.355

Gnomad4 SAS AF: 0.262

Gnomad4 FIN AF: 0.121

Gnomad4 NFE AF: 0.136

Gnomad4 OTH AF: 0.248

Alfa AF: 0.166 Hom.: 4176

Bravo AF: 0.273

Asia WGS AF: 0.306 AC: 1067 AN: 3478

EpiCase AF: 0.143

EpiControl AF: 0.140

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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)	Jul 31, 2012	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 26, 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. -

Bethlem myopathy 1A Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 30, 2021	- -

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

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Jun 23, 2017

- -

Dystonia 27 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

Collagen 6-related myopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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. -

Ullrich congenital muscular dystrophy 1A Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.31
Cadd	Benign	8.5
Dann	Benign	0.74

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: rs2646254; hg19: chr2-238267717; COSMIC: COSV55083693; COSMIC: COSV55083693;