rs112290343

Positions:

• chr2-237325642-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The ENST00000295550.9(COL6A3):​c.9411T>C​(p.Cys3137=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0168 in 1,614,142 control chromosomes in the GnomAD database, including 291 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (20 hom., cov: 32)
  • Exomes 𝑓: 0.017 (271 hom.)
• Consequence: COL6A3 ENST00000295550.9 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.0300

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=-0.81).
• BP6: Variant 2-237325642-A-G is Benign according to our data. Variant chr2-237325642-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 95021.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-237325642-A-G is described in Lovd as [Benign]. Variant chr2-237325642-A-G is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.03 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0139 (2121/152344) while in subpopulation AMR AF= 0.0253 (388/15308). AF 95% confidence interval is 0.0233. There are 20 homozygotes in gnomad4. There are 1004 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 20 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL6A3	NM_004369.4	c.9411T>C	p.Cys3137=	synonymous_variant	43/44	ENST00000295550.9	NP_004360.2
COL6A3	NM_057167.4	c.8793T>C	p.Cys2931=	synonymous_variant	42/43		NP_476508.2
COL6A3	NM_057166.5	c.7590T>C	p.Cys2530=	synonymous_variant	40/41		NP_476507.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL6A3	ENST00000295550.9	c.9411T>C	p.Cys3137=	synonymous_variant	43/44	1	NM_004369.4	ENSP00000295550	P1

Frequencies

GnomAD3 genomes AF: 0.0139 AC: 2119 AN: 152226 Hom.: 20 Cov.: 32

Gnomad AFR AF: 0.00410

Gnomad AMI AF: 0.0450

Gnomad AMR AF: 0.0254

Gnomad ASJ AF: 0.00576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00620

Gnomad FIN AF: 0.00508

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0199

Gnomad OTH AF: 0.0264

GnomAD3 exomes AF: 0.0137 AC: 3452 AN: 251458 Hom.: 35 AF XY: 0.0141 AC XY: 1912 AN XY: 135902

Gnomad AFR exome AF: 0.00215

Gnomad AMR exome AF: 0.0191

Gnomad ASJ exome AF: 0.00575

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00640

Gnomad FIN exome AF: 0.00508

Gnomad NFE exome AF: 0.0198

Gnomad OTH exome AF: 0.0222

GnomAD4 exome AF: 0.0171 AC: 25017 AN: 1461798 Hom.: 271 Cov.: 31 AF XY: 0.0169 AC XY: 12256 AN XY: 727200

Gnomad4 AFR exome AF: 0.00311

Gnomad4 AMR exome AF: 0.0201

Gnomad4 ASJ exome AF: 0.00559

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.00707

Gnomad4 FIN exome AF: 0.00509

Gnomad4 NFE exome AF: 0.0196

Gnomad4 OTH exome AF: 0.0174

GnomAD4 genome AF: 0.0139 AC: 2121 AN: 152344 Hom.: 20 Cov.: 32 AF XY: 0.0135 AC XY: 1004 AN XY: 74492

Gnomad4 AFR AF: 0.00409

Gnomad4 AMR AF: 0.0253

Gnomad4 ASJ AF: 0.00576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00621

Gnomad4 FIN AF: 0.00508

Gnomad4 NFE AF: 0.0199

Gnomad4 OTH AF: 0.0261

Alfa AF: 0.0159 Hom.: 10

Bravo AF: 0.0152

Asia WGS AF: 0.00520 AC: 18 AN: 3478

EpiCase AF: 0.0210

EpiControl AF: 0.0228

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 02, 2012	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 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	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 14, 2018	- -

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

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	1.4
DANN	Benign	0.60

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: rs112290343; hg19: chr2-238234285;