rs2291795

Positions:

chr2-237344422-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_004369.4(COL6A3):c.7596G>A(p.Lys2532=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.122 in 1,614,090 control chromosomes in the GnomAD database, including 12,659 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.13 ( 1390 hom., cov: 32)

Exomes 𝑓: 0.12 ( 11269 hom. )

Consequence

COL6A3
NM_004369.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 1.19

Variant links:

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]

COL6A3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.35).

BP6

Variant 2-237344422-C-T is Benign according to our data. Variant chr2-237344422-C-T is described in ClinVar as [Benign]. Clinvar id is 94990.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-237344422-C-T is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=1.19 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.173 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
COL6A3	NM_004369.4 linkuse as main transcript	c.7596G>A	p.Lys2532=	synonymous_variant	36/44	ENST00000295550.9
COL6A3	NM_057167.4 linkuse as main transcript	c.6978G>A	p.Lys2326=	synonymous_variant	35/43
COL6A3	NM_057166.5 linkuse as main transcript	c.5775G>A	p.Lys1925=	synonymous_variant	33/41

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL6A3	ENST00000295550.9 linkuse as main transcript	c.7596G>A	p.Lys2532=	synonymous_variant	36/44	1	NM_004369.4	P1	P12111-1

Frequencies

GnomAD3 genomes

AF:

0.131

AC:

19866

AN:

152092

Hom.:

1377

Cov.:

show subpopulations

Gnomad AFR

AF:

0.170

Gnomad AMI

AF:

0.0921

Gnomad AMR

AF:

0.121

Gnomad ASJ

AF:

0.123

Gnomad EAS

AF:

0.183

Gnomad SAS

AF:

0.178

Gnomad FIN

AF:

0.0846

Gnomad MID

AF:

0.0823

Gnomad NFE

AF:

0.110

Gnomad OTH

AF:

0.116

GnomAD3 exomes

AF:

0.128

AC:

32192

AN:

251394

Hom.:

2240

AF XY:

0.128

AC XY:

17351

AN XY:

135860

show subpopulations

Gnomad AFR exome

AF:

0.169

Gnomad AMR exome

AF:

0.128

Gnomad ASJ exome

AF:

0.130

Gnomad EAS exome

AF:

0.174

Gnomad SAS exome

AF:

0.178

Gnomad FIN exome

AF:

0.0863

Gnomad NFE exome

AF:

0.110

Gnomad OTH exome

AF:

0.118

GnomAD4 exome

AF:

0.121

AC:

176814

AN:

1461880

Hom.:

11269

Cov.:

AF XY:

0.122

AC XY:

88755

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.170

Gnomad4 AMR exome

AF:

0.129

Gnomad4 ASJ exome

AF:

0.120

Gnomad4 EAS exome

AF:

0.164

Gnomad4 SAS exome

AF:

0.178

Gnomad4 FIN exome

AF:

0.0894

Gnomad4 NFE exome

AF:

0.114

Gnomad4 OTH exome

AF:

0.138

GnomAD4 genome

AF:

0.131

AC:

19918

AN:

152210

Hom.:

1390

Cov.:

AF XY:

0.129

AC XY:

9574

AN XY:

74412

show subpopulations

Gnomad4 AFR

AF:

0.170

Gnomad4 AMR

AF:

0.122

Gnomad4 ASJ

AF:

0.123

Gnomad4 EAS

AF:

0.183

Gnomad4 SAS

AF:

0.179

Gnomad4 FIN

AF:

0.0846

Gnomad4 NFE

AF:

0.110

Gnomad4 OTH

AF:

0.123

Alfa

AF:

0.116

Hom.:

1546

Bravo

AF:

0.137

Asia WGS

AF:

0.196

AC:

683

AN:

3478

EpiCase

AF:

0.115

EpiControl

AF:

0.111

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

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)	Aug 07, 2012	- -
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 34% 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: 32. Only high quality variants are reported. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 25, 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	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Jun 19, 2017

- -

Collagen 6-related myopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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

Jan 31, 2024

- -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.35

CADD

Benign

8.1

DANN

Benign

0.51

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over