rs34181055

Positions:

chr2-237344509-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_004369.4(COL6A3):c.7509G>A(p.Arg2503Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0331 in 1,614,188 control chromosomes in the GnomAD database, including 1,038 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.025 ( 72 hom., cov: 32)

Exomes 𝑓: 0.034 ( 966 hom. )

Consequence

COL6A3
NM_004369.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 0.226

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=-0.78).

BP6

Variant 2-237344509-C-T is Benign according to our data. Variant chr2-237344509-C-T is described in ClinVar as [Benign]. Clinvar id is 94988.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-237344509-C-T is described in Lovd as [Benign]. Variant chr2-237344509-C-T is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=0.226 with no splicing effect.

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0246 (3753/152300) while in subpopulation SAS AF= 0.0388 (187/4816). AF 95% confidence interval is 0.0343. There are 72 homozygotes in gnomad4. There are 1856 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 72 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL6A3	NM_004369.4 linkuse as main transcript	c.7509G>A	p.Arg2503Arg	synonymous_variant	36/44	ENST00000295550.9	NP_004360.2	P12111-1D9ZGF2Q8N4Z1Q63HQ4
COL6A3	NM_057167.4 linkuse as main transcript	c.6891G>A	p.Arg2297Arg	synonymous_variant	35/43		NP_476508.2	P12111-2Q8N4Z1Q63HQ4
COL6A3	NM_057166.5 linkuse as main transcript	c.5688G>A	p.Arg1896Arg	synonymous_variant	33/41		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.7509G>A	p.Arg2503Arg	synonymous_variant	36/44	1	NM_004369.4	ENSP00000295550.4		P12111-1

Frequencies

GnomAD3 genomes

AF:

0.0247

AC:

3755

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00634

Gnomad AMI

AF:

0.0549

Gnomad AMR

AF:

0.0152

Gnomad ASJ

AF:

0.0271

Gnomad EAS

AF:

0.00944

Gnomad SAS

AF:

0.0388

Gnomad FIN

AF:

0.0418

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0351

Gnomad OTH

AF:

0.0211

GnomAD3 exomes

AF:

0.0287

AC:

7212

AN:

251418

Hom.:

137

AF XY:

0.0305

AC XY:

4146

AN XY:

135872

show subpopulations

Gnomad AFR exome

AF:

0.00591

Gnomad AMR exome

AF:

0.0119

Gnomad ASJ exome

AF:

0.0264

Gnomad EAS exome

AF:

0.0104

Gnomad SAS exome

AF:

0.0396

Gnomad FIN exome

AF:

0.0396

Gnomad NFE exome

AF:

0.0353

Gnomad OTH exome

AF:

0.0259

GnomAD4 exome

AF:

0.0339

AC:

49616

AN:

1461888

Hom.:

966

Cov.:

AF XY:

0.0342

AC XY:

24858

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.00454

Gnomad4 AMR exome

AF:

0.0128

Gnomad4 ASJ exome

AF:

0.0274

Gnomad4 EAS exome

AF:

0.00992

Gnomad4 SAS exome

AF:

0.0395

Gnomad4 FIN exome

AF:

0.0399

Gnomad4 NFE exome

AF:

0.0362

Gnomad4 OTH exome

AF:

0.0312

GnomAD4 genome

AF:

0.0246

AC:

3753

AN:

152300

Hom.:

Cov.:

AF XY:

0.0249

AC XY:

1856

AN XY:

74462

show subpopulations

Gnomad4 AFR

AF:

0.00633

Gnomad4 AMR

AF:

0.0152

Gnomad4 ASJ

AF:

0.0271

Gnomad4 EAS

AF:

0.00946

Gnomad4 SAS

AF:

0.0388

Gnomad4 FIN

AF:

0.0418

Gnomad4 NFE

AF:

0.0351

Gnomad4 OTH

AF:

0.0204

Alfa

AF:

0.0309

Hom.:

Bravo

AF:

0.0224

Asia WGS

AF:

0.0360

AC:

126

AN:

3478

EpiCase

AF:

0.0328

EpiControl

AF:

0.0311

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:8

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 19, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 19, 2012	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
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	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 22, 2015	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	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.78

CADD

Benign

1.8

DANN

Benign

0.48

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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