rs2646258

Positions:

• chr2-237344506-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_004369.4(COL6A3):​c.7512C>T​(p.Asn2504=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.104 in 1,614,070 control chromosomes in the GnomAD database, including 9,107 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (904 hom., cov: 32)
  • Exomes 𝑓: 0.10 (8203 hom.)
• Consequence: COL6A3 NM_004369.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -3.08

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 2-237344506-G-A is Benign according to our data. Variant chr2-237344506-G-A is described in ClinVar as [Benign]. Clinvar id is 94989.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-237344506-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-3.08 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.156 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL6A3	NM_004369.4	c.7512C>T	p.Asn2504=	synonymous_variant	36/44	ENST00000295550.9	NP_004360.2
COL6A3	NM_057167.4	c.6894C>T	p.Asn2298=	synonymous_variant	35/43		NP_476508.2
COL6A3	NM_057166.5	c.5691C>T	p.Asn1897=	synonymous_variant	33/41		NP_476507.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL6A3	ENST00000295550.9	c.7512C>T	p.Asn2504=	synonymous_variant	36/44	1	NM_004369.4	ENSP00000295550	P1

Frequencies

GnomAD3 genomes AF: 0.106 AC: 16132 AN: 152098 Hom.: 904 Cov.: 32

Gnomad AFR AF: 0.0948

Gnomad AMI AF: 0.0888

Gnomad AMR AF: 0.161

Gnomad ASJ AF: 0.131

Gnomad EAS AF: 0.0494

Gnomad SAS AF: 0.118

Gnomad FIN AF: 0.111

Gnomad MID AF: 0.180

Gnomad NFE AF: 0.102

Gnomad OTH AF: 0.118

GnomAD3 exomes AF: 0.113 AC: 28379 AN: 251384 Hom.: 1717 AF XY: 0.112 AC XY: 15264 AN XY: 135854

Gnomad AFR exome AF: 0.0941

Gnomad AMR exome AF: 0.170

Gnomad ASJ exome AF: 0.127

Gnomad EAS exome AF: 0.0472

Gnomad SAS exome AF: 0.121

Gnomad FIN exome AF: 0.113

Gnomad NFE exome AF: 0.105

Gnomad OTH exome AF: 0.114

GnomAD4 exome AF: 0.104 AC: 152269 AN: 1461854 Hom.: 8203 Cov.: 34 AF XY: 0.105 AC XY: 76074 AN XY: 727232

Gnomad4 AFR exome AF: 0.0957

Gnomad4 AMR exome AF: 0.171

Gnomad4 ASJ exome AF: 0.121

Gnomad4 EAS exome AF: 0.0533

Gnomad4 SAS exome AF: 0.119

Gnomad4 FIN exome AF: 0.110

Gnomad4 NFE exome AF: 0.102

Gnomad4 OTH exome AF: 0.103

GnomAD4 genome AF: 0.106 AC: 16138 AN: 152216 Hom.: 904 Cov.: 32 AF XY: 0.109 AC XY: 8082 AN XY: 74410

Gnomad4 AFR AF: 0.0947

Gnomad4 AMR AF: 0.162

Gnomad4 ASJ AF: 0.131

Gnomad4 EAS AF: 0.0493

Gnomad4 SAS AF: 0.117

Gnomad4 FIN AF: 0.111

Gnomad4 NFE AF: 0.102

Gnomad4 OTH AF: 0.116

Alfa AF: 0.104 Hom.: 422

Bravo AF: 0.108

Asia WGS AF: 0.0800 AC: 279 AN: 3478

EpiCase AF: 0.110

EpiControl AF: 0.107

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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 38% 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: 35. Only high quality variants are reported. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 31, 2012	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Jun 19, 2017

- -

Bethlem myopathy 1A Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.043
DANN	Benign	0.41

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: rs2646258; hg19: chr2-238253149; COSMIC: COSV55093450; COSMIC: COSV55093450;