2-237340987-C-T

Position:

chr2-237340987-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_004369.4(COL6A3):c.7929G>A(p.Ala2643Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.399 in 1,613,868 control chromosomes in the GnomAD database, including 131,268 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.37 ( 11313 hom., cov: 32)

Exomes 𝑓: 0.40 ( 119955 hom. )

Consequence

COL6A3
NM_004369.4 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.131

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:

COL6A3 (HGNC:):

COL6A3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.54).

BP6

Variant 2-237340987-C-T is Benign according to our data. Variant chr2-237340987-C-T is described in ClinVar as [Benign]. Clinvar id is 94998.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-237340987-C-T is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-0.131 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.461 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL6A3	NM_004369.4 linkuse as main transcript	c.7929G>A	p.Ala2643Ala	synonymous_variant	38/44	ENST00000295550.9	NP_004360.2	P12111-1D9ZGF2Q8N4Z1Q63HQ4
COL6A3	NM_057167.4 linkuse as main transcript	c.7311G>A	p.Ala2437Ala	synonymous_variant	37/43		NP_476508.2	P12111-2Q8N4Z1Q63HQ4
COL6A3	NM_057166.5 linkuse as main transcript	c.6108G>A	p.Ala2036Ala	synonymous_variant	35/41		NP_476507.3	P12111-4B7ZW00

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL6A3	ENST00000295550.9 linkuse as main transcript	c.7929G>A	p.Ala2643Ala	synonymous_variant	38/44	1	NM_004369.4	ENSP00000295550.4		P12111-1

Frequencies

GnomAD3 genomes

AF:

0.374

AC:

56772

AN:

151910

Hom.:

11317

Cov.:

show subpopulations

Gnomad AFR

AF:

0.252

Gnomad AMI

AF:

0.536

Gnomad AMR

AF:

0.363

Gnomad ASJ

AF:

0.454

Gnomad EAS

AF:

0.477

Gnomad SAS

AF:

0.334

Gnomad FIN

AF:

0.508

Gnomad MID

AF:

0.481

Gnomad NFE

AF:

0.416

Gnomad OTH

AF:

0.403

GnomAD3 exomes

AF:

0.396

AC:

99511

AN:

250988

Hom.:

20535

AF XY:

0.400

AC XY:

54314

AN XY:

135628

show subpopulations

Gnomad AFR exome

AF:

0.248

Gnomad AMR exome

AF:

0.318

Gnomad ASJ exome

AF:

0.442

Gnomad EAS exome

AF:

0.476

Gnomad SAS exome

AF:

0.332

Gnomad FIN exome

AF:

0.497

Gnomad NFE exome

AF:

0.421

Gnomad OTH exome

AF:

0.429

GnomAD4 exome

AF:

0.402

AC:

587666

AN:

1461842

Hom.:

119955

Cov.:

AF XY:

0.401

AC XY:

291804

AN XY:

727222

show subpopulations

Gnomad4 AFR exome

AF:

0.249

Gnomad4 AMR exome

AF:

0.324

Gnomad4 ASJ exome

AF:

0.446

Gnomad4 EAS exome

AF:

0.505

Gnomad4 SAS exome

AF:

0.334

Gnomad4 FIN exome

AF:

0.491

Gnomad4 NFE exome

AF:

0.406

Gnomad4 OTH exome

AF:

0.400

GnomAD4 genome

AF:

0.374

AC:

56783

AN:

152026

Hom.:

11313

Cov.:

AF XY:

0.379

AC XY:

28173

AN XY:

74296

show subpopulations

Gnomad4 AFR

AF:

0.252

Gnomad4 AMR

AF:

0.362

Gnomad4 ASJ

AF:

0.454

Gnomad4 EAS

AF:

0.477

Gnomad4 SAS

AF:

0.334

Gnomad4 FIN

AF:

0.508

Gnomad4 NFE

AF:

0.416

Gnomad4 OTH

AF:

0.402

Alfa

AF:

0.388

Hom.:

12786

Bravo

AF:

0.358

Asia WGS

AF:

0.384

AC:

1336

AN:

3478

EpiCase

AF:

0.417

EpiControl

AF:

0.424

ClinVar

Significance: Benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:8

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	PreventionGenetics, part of Exact Sciences	-	- -
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. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 09, 2012	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -
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	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

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	- -

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. -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Ullrich congenital muscular dystrophy 1A

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.54

CADD

Benign

9.3

DANN

Benign

0.57

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