rs2646254

Positions:

chr2-237359074-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBA1

The NM_004369.4(COL6A3):c.6369G>A(p.Leu2123=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.173 in 1,612,952 control chromosomes in the GnomAD database, including 30,488 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.25 ( 6552 hom., cov: 33)

Exomes 𝑓: 0.16 ( 23936 hom. )

Consequence

COL6A3
NM_004369.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: -0.0350

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 -18 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.31).

BP6

Variant 2-237359074-C-T is Benign according to our data. Variant chr2-237359074-C-T is described in ClinVar as [Benign]. Clinvar id is 94962.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-237359074-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.463 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
COL6A3	NM_004369.4 linkuse as main transcript	c.6369G>A	p.Leu2123=	synonymous_variant	20/44	ENST00000295550.9
COL6A3	NM_057167.4 linkuse as main transcript	c.5751G>A	p.Leu1917=	synonymous_variant	19/43
COL6A3	NM_057166.5 linkuse as main transcript	c.4548G>A	p.Leu1516=	synonymous_variant	17/41

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL6A3	ENST00000295550.9 linkuse as main transcript	c.6369G>A	p.Leu2123=	synonymous_variant	20/44	1	NM_004369.4	P1	P12111-1
COL6A3	ENST00000472056.5 linkuse as main transcript	c.4548G>A	p.Leu1516=	synonymous_variant	17/41	1			P12111-4
COL6A3	ENST00000353578.9 linkuse as main transcript	c.5751G>A	p.Leu1917=	synonymous_variant	19/43	5			P12111-2

Frequencies

GnomAD3 genomes

AF:

0.253

AC:

38527

AN:

152028

Hom.:

6518

Cov.:

show subpopulations

Gnomad AFR

AF:

0.468

Gnomad AMI

AF:

0.139

Gnomad AMR

AF:

0.277

Gnomad ASJ

AF:

0.172

Gnomad EAS

AF:

0.355

Gnomad SAS

AF:

0.261

Gnomad FIN

AF:

0.121

Gnomad MID

AF:

0.253

Gnomad NFE

AF:

0.136

Gnomad OTH

AF:

0.244

GnomAD3 exomes

AF:

0.213

AC:

53684

AN:

251486

Hom.:

7147

AF XY:

0.206

AC XY:

27961

AN XY:

135918

show subpopulations

Gnomad AFR exome

AF:

0.487

Gnomad AMR exome

AF:

0.289

Gnomad ASJ exome

AF:

0.170

Gnomad EAS exome

AF:

0.360

Gnomad SAS exome

AF:

0.253

Gnomad FIN exome

AF:

0.127

Gnomad NFE exome

AF:

0.139

Gnomad OTH exome

AF:

0.179

GnomAD4 exome

AF:

0.165

AC:

240631

AN:

1460806

Hom.:

23936

Cov.:

AF XY:

0.166

AC XY:

120329

AN XY:

726750

show subpopulations

Gnomad4 AFR exome

AF:

0.489

Gnomad4 AMR exome

AF:

0.288

Gnomad4 ASJ exome

AF:

0.163

Gnomad4 EAS exome

AF:

0.335

Gnomad4 SAS exome

AF:

0.251

Gnomad4 FIN exome

AF:

0.124

Gnomad4 NFE exome

AF:

0.138

Gnomad4 OTH exome

AF:

0.187

GnomAD4 genome

AF:

0.254

AC:

38623

AN:

152146

Hom.:

6552

Cov.:

AF XY:

0.256

AC XY:

19024

AN XY:

74396

show subpopulations

Gnomad4 AFR

AF:

0.468

Gnomad4 AMR

AF:

0.278

Gnomad4 ASJ

AF:

0.172

Gnomad4 EAS

AF:

0.355

Gnomad4 SAS

AF:

0.262

Gnomad4 FIN

AF:

0.121

Gnomad4 NFE

AF:

0.136

Gnomad4 OTH

AF:

0.248

Alfa

AF:

0.166

Hom.:

4176

Bravo

AF:

0.273

Asia WGS

AF:

0.306

AC:

1067

AN:

3478

EpiCase

AF:

0.143

EpiControl

AF:

0.140

ClinVar

Significance: Benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 26, 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, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 31, 2012	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -
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	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
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 49% 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: 46. Only high quality variants are reported. -

Bethlem myopathy 1A

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 30, 2021	- -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Jun 23, 2017

- -

Dystonia 27

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

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. -

Ullrich congenital muscular dystrophy 1A

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

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

-0.31

CADD

Benign

8.5

DANN

Benign

0.74

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