rs10201909

chr2-237334726-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.9129C>T(p.Arg3043=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0261 in 1,613,994 control chromosomes in the GnomAD database, including 1,633 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.063 (695 hom., cov: 32)
  • Exomes 𝑓: 0.022 (938 hom.)
• Consequence: COL6A3 NM_004369.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -2.59

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=-0.8).
• BP6: Variant 2-237334726-G-A is Benign according to our data. Variant chr2-237334726-G-A is described in ClinVar as [Benign]. Clinvar id is 95017.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-237334726-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-2.59 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) 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.9129C>T	p.Arg3043=	synonymous_variant	41/44	ENST00000295550.9
COL6A3	NM_057167.4	c.8511C>T	p.Arg2837=	synonymous_variant	40/43
COL6A3	NM_057166.5	c.7308C>T	p.Arg2436=	synonymous_variant	38/41

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL6A3	ENST00000295550.9	c.9129C>T	p.Arg3043=	synonymous_variant	41/44	1	NM_004369.4	P1

Frequencies

GnomAD3 genomes AF: 0.0632 AC: 9608 AN: 152052 Hom.: 695 Cov.: 32

Gnomad AFR AF: 0.177

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0365

Gnomad ASJ AF: 0.0274

Gnomad EAS AF: 0.00425

Gnomad SAS AF: 0.0220

Gnomad FIN AF: 0.00735

Gnomad MID AF: 0.0601

Gnomad NFE AF: 0.0190

Gnomad OTH AF: 0.0604

GnomAD3 exomes AF: 0.0313 AC: 7863 AN: 251444 Hom.: 353 AF XY: 0.0288 AC XY: 3915 AN XY: 135908

Gnomad AFR exome AF: 0.189

Gnomad AMR exome AF: 0.0250

Gnomad ASJ exome AF: 0.0320

Gnomad EAS exome AF: 0.00413

Gnomad SAS exome AF: 0.0259

Gnomad FIN exome AF: 0.00735

Gnomad NFE exome AF: 0.0212

Gnomad OTH exome AF: 0.0285

GnomAD4 exome AF: 0.0223 AC: 32559 AN: 1461824 Hom.: 938 Cov.: 58 AF XY: 0.0219 AC XY: 15936 AN XY: 727210

Gnomad4 AFR exome AF: 0.187

Gnomad4 AMR exome AF: 0.0259

Gnomad4 ASJ exome AF: 0.0331

Gnomad4 EAS exome AF: 0.00189

Gnomad4 SAS exome AF: 0.0251

Gnomad4 FIN exome AF: 0.00887

Gnomad4 NFE exome AF: 0.0173

Gnomad4 OTH exome AF: 0.0316

GnomAD4 genome AF: 0.0632 AC: 9618 AN: 152170 Hom.: 695 Cov.: 32 AF XY: 0.0610 AC XY: 4536 AN XY: 74418

Gnomad4 AFR AF: 0.177

Gnomad4 AMR AF: 0.0364

Gnomad4 ASJ AF: 0.0274

Gnomad4 EAS AF: 0.00406

Gnomad4 SAS AF: 0.0220

Gnomad4 FIN AF: 0.00735

Gnomad4 NFE AF: 0.0190

Gnomad4 OTH AF: 0.0598

Alfa AF: 0.0410 Hom.: 160

Bravo AF: 0.0712

Asia WGS AF: 0.0230 AC: 81 AN: 3478

EpiCase AF: 0.0235

EpiControl AF: 0.0249

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

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 17, 2012	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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+	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 23, 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. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 20, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

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. -

Bethlem myopathy 1A Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
Cadd	Benign	0.062
Dann	Benign	0.38

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: rs10201909; hg19: chr2-238243369; COSMIC: COSV55090232; COSMIC: COSV55090232;