2-237339091-C-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_004369.4(COL6A3):c.8491G>C(p.Asp2831His) variant causes a missense change. The variant allele was found at a frequency of 0.0831 in 1,612,822 control chromosomes in the GnomAD database, including 6,300 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D2831Y) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.059 ( 369 hom., cov: 33)

Exomes 𝑓: 0.086 ( 5931 hom. )

Consequence

COL6A3
NM_004369.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 5.46

Publications

15 publications found

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 Gene-Disease associations (from GenCC):

Bethlem myopathy 1A
Inheritance: AD, AR, SD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Ambry Genetics
collagen 6-related myopathy
Inheritance: AD, AR Classification: DEFINITIVE Submitted by: ClinGen
Ullrich congenital muscular dystrophy 1C
Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
dystonia 27
Inheritance: AR Classification: STRONG, SUPPORTIVE, LIMITED, NO_KNOWN Submitted by: Illumina, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics, Orphanet
Ullrich congenital muscular dystrophy 1A
Inheritance: AR, AD, SD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp
Bethlem myopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Ullrich congenital muscular dystrophy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

COL6A3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0027243495).

BP6

Variant 2-237339091-C-G is Benign according to our data. Variant chr2-237339091-C-G is described in ClinVar as Benign. ClinVar VariationId is 95006.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.088 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
COL6A3	NM_004369.4 link	c.8491G>C	p.Asp2831His	missense_variant	Exon 39 of 44	ENST00000295550.9	NP_004360.2
COL6A3	NM_057167.4 link	c.7873G>C	p.Asp2625His	missense_variant	Exon 38 of 43		NP_476508.2
COL6A3	NM_057166.5 link	c.6670G>C	p.Asp2224His	missense_variant	Exon 36 of 41		NP_476507.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL6A3	ENST00000295550.9 link	c.8491G>C	p.Asp2831His	missense_variant	Exon 39 of 44	1	NM_004369.4	ENSP00000295550.4

Frequencies

GnomAD3 genomes

AF:

0.0589

AC:

8959

AN:

152024

Hom.:

367

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0173

Gnomad AMI

AF:

0.0329

Gnomad AMR

AF:

0.0454

Gnomad ASJ

AF:

0.0931

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.0700

Gnomad FIN

AF:

0.0583

Gnomad MID

AF:

0.0696

Gnomad NFE

AF:

0.0899

Gnomad OTH

AF:

0.0523

GnomAD2 exomes

AF:

0.0655

AC:

16463

AN:

251286

AF XY:

0.0689

show subpopulations

Gnomad AFR exome

AF:

0.0145

Gnomad AMR exome

AF:

0.0322

Gnomad ASJ exome

AF:

0.0971

Gnomad EAS exome

AF:

0.000272

Gnomad FIN exome

AF:

0.0594

Gnomad NFE exome

AF:

0.0894

Gnomad OTH exome

AF:

0.0737

GnomAD4 exome

AF:

0.0856

AC:

125027

AN:

1460680

Hom.:

5931

Cov.:

AF XY:

0.0857

AC XY:

62301

AN XY:

726710

show subpopulations

African (AFR)

AF:

0.0127

AC:

424

AN:

33478

American (AMR)

AF:

0.0339

AC:

1516

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.0912

AC:

2383

AN:

26128

East Asian (EAS)

AF:

0.000302

AC:

AN:

39692

South Asian (SAS)

AF:

0.0754

AC:

6500

AN:

86212

European-Finnish (FIN)

AF:

0.0622

AC:

3323

AN:

53400

Middle Eastern (MID)

AF:

0.0928

AC:

535

AN:

5764

European-Non Finnish (NFE)

AF:

0.0944

AC:

104915

AN:

1110926

Other (OTH)

AF:

0.0898

AC:

5419

AN:

60370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

4909

9818

14726

19635

24544

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3844

7688

11532

15376

19220

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0589

AC:

8961

AN:

152142

Hom.:

369

Cov.:

AF XY:

0.0551

AC XY:

4095

AN XY:

74358

show subpopulations

African (AFR)

AF:

0.0172

AC:

716

AN:

41510

American (AMR)

AF:

0.0453

AC:

692

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.0931

AC:

323

AN:

3470

East Asian (EAS)

AF:

0.000386

AC:

AN:

5178

South Asian (SAS)

AF:

0.0709

AC:

341

AN:

4810

European-Finnish (FIN)

AF:

0.0583

AC:

617

AN:

10588

Middle Eastern (MID)

AF:

0.0714

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0899

AC:

6112

AN:

67982

Other (OTH)

AF:

0.0508

AC:

107

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

428

856

1285

1713

2141

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

114

228

342

456

570

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0787

Hom.:

437

Bravo

AF:

0.0575

ESP6500AA

AF:

0.0188

AC:

ESP6500EA

AF:

0.0992

AC:

853

ExAC

AF:

0.0671

AC:

8147

Asia WGS

AF:

0.0290

AC:

103

AN:

3478

EpiCase

AF:

0.0963

EpiControl

AF:

0.0930

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 25, 2016

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Aug 07, 2012

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 15, 2013

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:2

Aug 25, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Bethlem myopathy 1A

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Collagen 6-related myopathy

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.47

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.12

CADD

Uncertain

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.18

.;T;.;T;.

Eigen

Pathogenic

0.72

Eigen_PC

Pathogenic

0.70

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.92

D;D;D;D;.

MetaRNN

Benign

0.0027

T;T;T;T;T

MetaSVM

Benign

-0.41

MutationAssessor

Uncertain

2.7

.;M;.;.;.

PhyloP100

5.5

PrimateAI

Benign

0.38

PROVEAN

Uncertain

-2.7

D;D;N;.;D

REVEL

Uncertain

0.54

Sift

Uncertain

0.0030

D;D;D;.;D

Sift4G

Pathogenic

0.0

D;D;D;D;D

Polyphen

1.0

D;D;.;.;D

Vest4

0.30

MPC

0.18

ClinPred

0.038

GERP RS

5.1

Varity_R

0.31

gMVP

0.51

Mutation Taster

=92/8

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over