2-237340465-T-C

Position:

• chr2-237340465-T-C

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.8451A>G​(p.Pro2817Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0945 in 1,612,866 control chromosomes in the GnomAD database, including 8,121 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.069 (472 hom., cov: 32)
  • Exomes 𝑓: 0.097 (7649 hom.)
• Consequence: COL6A3 NM_004369.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -6.63

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=-1.02).
• BP6: Variant 2-237340465-T-C is Benign according to our data. Variant chr2-237340465-T-C is described in ClinVar as [Benign]. Clinvar id is 95003.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-237340465-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-6.63 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.1 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL6A3	NM_004369.4	c.8451A>G	p.Pro2817Pro	synonymous_variant	38/44	ENST00000295550.9	NP_004360.2
COL6A3	NM_057167.4	c.7833A>G	p.Pro2611Pro	synonymous_variant	37/43		NP_476508.2
COL6A3	NM_057166.5	c.6630A>G	p.Pro2210Pro	synonymous_variant	35/41		NP_476507.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL6A3	ENST00000295550.9	c.8451A>G	p.Pro2817Pro	synonymous_variant	38/44	1	NM_004369.4	ENSP00000295550.4

Frequencies

GnomAD3 genomes AF: 0.0687 AC: 10451 AN: 152150 Hom.: 472 Cov.: 32

Gnomad AFR AF: 0.0189

Gnomad AMI AF: 0.139

Gnomad AMR AF: 0.0489

Gnomad ASJ AF: 0.105

Gnomad EAS AF: 0.00945

Gnomad SAS AF: 0.0636

Gnomad FIN AF: 0.0914

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.102

Gnomad OTH AF: 0.0641

GnomAD3 exomes AF: 0.0745 AC: 18646 AN: 250156 Hom.: 868 AF XY: 0.0770 AC XY: 10427 AN XY: 135338

Gnomad AFR exome AF: 0.0177

Gnomad AMR exome AF: 0.0391

Gnomad ASJ exome AF: 0.107

Gnomad EAS exome AF: 0.0101

Gnomad SAS exome AF: 0.0636

Gnomad FIN exome AF: 0.0934

Gnomad NFE exome AF: 0.101

Gnomad OTH exome AF: 0.0743

GnomAD4 exome AF: 0.0972 AC: 141954 AN: 1460598 Hom.: 7649 Cov.: 32 AF XY: 0.0963 AC XY: 69948 AN XY: 726676

Gnomad4 AFR exome AF: 0.0158

Gnomad4 AMR exome AF: 0.0413

Gnomad4 ASJ exome AF: 0.111

Gnomad4 EAS exome AF: 0.00967

Gnomad4 SAS exome AF: 0.0650

Gnomad4 FIN exome AF: 0.0925

Gnomad4 NFE exome AF: 0.108

Gnomad4 OTH exome AF: 0.0889

GnomAD4 genome AF: 0.0686 AC: 10445 AN: 152268 Hom.: 472 Cov.: 32 AF XY: 0.0669 AC XY: 4978 AN XY: 74452

Gnomad4 AFR AF: 0.0188

Gnomad4 AMR AF: 0.0488

Gnomad4 ASJ AF: 0.105

Gnomad4 EAS AF: 0.00947

Gnomad4 SAS AF: 0.0634

Gnomad4 FIN AF: 0.0914

Gnomad4 NFE AF: 0.102

Gnomad4 OTH AF: 0.0629

Alfa AF: 0.0897 Hom.: 345

Bravo AF: 0.0647

Asia WGS AF: 0.0430 AC: 151 AN: 3478

EpiCase AF: 0.101

EpiControl AF: 0.0999

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	Eurofins Ntd Llc (ga)	Aug 07, 2012	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
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, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 05, 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	Sep 13, 2017	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Bethlem myopathy 1A Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 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	-1.0
CADD	Benign	0.0020
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: rs61729844; hg19: chr2-238249108; COSMIC: COSV55108426;