2-237368736-C-T

Position:

chr2-237368736-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_004369.4(COL6A3):c.4727G>A(p.Arg1576Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0154 in 1,614,182 control chromosomes in the GnomAD database, including 244 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.010 ( 18 hom., cov: 32)

Exomes 𝑓: 0.016 ( 226 hom. )

Consequence

COL6A3
NM_004369.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.15

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0046691597).

BP6

Variant 2-237368736-C-T is Benign according to our data. Variant chr2-237368736-C-T is described in ClinVar as [Benign]. Clinvar id is 94938.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-237368736-C-T is described in Lovd as [Benign]. Variant chr2-237368736-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0105 (1593/152288) while in subpopulation NFE AF= 0.0172 (1171/68012). AF 95% confidence interval is 0.0164. There are 18 homozygotes in gnomad4. There are 757 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 18 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
COL6A3	NM_004369.4 linkuse as main transcript	c.4727G>A	p.Arg1576Gln	missense_variant	10/44	ENST00000295550.9	NP_004360.2
COL6A3	NM_057167.4 linkuse as main transcript	c.4109G>A	p.Arg1370Gln	missense_variant	9/43		NP_476508.2
COL6A3	NM_057166.5 linkuse as main transcript	c.2906G>A	p.Arg969Gln	missense_variant	7/41		NP_476507.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL6A3	ENST00000295550.9 linkuse as main transcript	c.4727G>A	p.Arg1576Gln	missense_variant	10/44	1	NM_004369.4	ENSP00000295550	P1	P12111-1
COL6A3	ENST00000472056.5 linkuse as main transcript	c.2906G>A	p.Arg969Gln	missense_variant	7/41	1		ENSP00000418285		P12111-4
COL6A3	ENST00000353578.9 linkuse as main transcript	c.4109G>A	p.Arg1370Gln	missense_variant	9/43	5		ENSP00000315873		P12111-2
COL6A3	ENST00000684597.1 linkuse as main transcript	c.117-60G>A		intron_variant				ENSP00000508021

Frequencies

GnomAD3 genomes

AF:

0.0105

AC:

1594

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00299

Gnomad AMI

AF:

0.0340

Gnomad AMR

AF:

0.0119

Gnomad ASJ

AF:

0.000864

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.00352

Gnomad FIN

AF:

0.00433

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0172

Gnomad OTH

AF:

0.00621

GnomAD3 exomes

AF:

0.00994

AC:

2501

AN:

251486

Hom.:

AF XY:

0.0103

AC XY:

1400

AN XY:

135920

show subpopulations

Gnomad AFR exome

AF:

0.00246

Gnomad AMR exome

AF:

0.00529

Gnomad ASJ exome

AF:

0.00119

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00510

Gnomad FIN exome

AF:

0.00568

Gnomad NFE exome

AF:

0.0170

Gnomad OTH exome

AF:

0.00896

GnomAD4 exome

AF:

0.0159

AC:

23304

AN:

1461894

Hom.:

226

Cov.:

AF XY:

0.0156

AC XY:

11324

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.00245

Gnomad4 AMR exome

AF:

0.00537

Gnomad4 ASJ exome

AF:

0.00134

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00552

Gnomad4 FIN exome

AF:

0.00569

Gnomad4 NFE exome

AF:

0.0192

Gnomad4 OTH exome

AF:

0.0120

GnomAD4 genome

AF:

0.0105

AC:

1593

AN:

152288

Hom.:

Cov.:

AF XY:

0.0102

AC XY:

757

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.00298

Gnomad4 AMR

AF:

0.0119

Gnomad4 ASJ

AF:

0.000864

Gnomad4 EAS

AF:

0.000387

Gnomad4 SAS

AF:

0.00373

Gnomad4 FIN

AF:

0.00433

Gnomad4 NFE

AF:

0.0172

Gnomad4 OTH

AF:

0.00615

Alfa

AF:

0.0154

Hom.:

Bravo

AF:

0.0106

TwinsUK

AF:

0.0191

AC:

ALSPAC

AF:

0.0210

AC:

ESP6500AA

AF:

0.00204

AC:

ESP6500EA

AF:

0.0156

AC:

134

ExAC

AF:

0.0103

AC:

1246

Asia WGS

AF:

0.00289

AC:

AN:

3478

EpiCase

AF:

0.0154

EpiControl

AF:

0.0154

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 05, 2012	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 29, 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	PreventionGenetics, part of Exact Sciences	-	- -
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+	-	- -

not provided

Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Jun 28, 2017

- -

Collagen 6-related myopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 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

AlphaMissense

Benign

0.092

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.31

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.21

.;T;.;T;.

Eigen

Benign

-0.33

Eigen_PC

Benign

-0.42

FATHMM_MKL

Benign

0.18

LIST_S2

Uncertain

0.90

D;D;D;D;.

MetaRNN

Benign

0.0047

T;T;T;T;T

MetaSVM

Benign

-0.67

MutationAssessor

Benign

0.90

.;L;.;.;.

MutationTaster

Benign

1.0

N;N;N;N;N;N

PrimateAI

Benign

0.33

PROVEAN

Benign

-1.8

N;N;N;.;N

REVEL

Benign

0.28

Sift

Benign

0.073

T;T;T;.;T

Sift4G

Uncertain

0.024

D;D;D;D;D

Polyphen

1.0

D;P;.;.;D

Vest4

0.23

MPC

0.38

ClinPred

0.014

GERP RS

4.5

Varity_R

0.21

gMVP

0.72

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