2-237334821-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.9034G>C(p.Ala3012Pro) variant causes a missense change. The variant allele was found at a frequency of 0.77 in 1,614,032 control chromosomes in the GnomAD database, including 480,817 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.81 ( 51127 hom., cov: 32)

Exomes 𝑓: 0.77 ( 429690 hom. )

Consequence

COL6A3
NM_004369.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:15

Conservation

PhyloP100: 5.63

Publications

40 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=7.71305E-7).

BP6

Variant 2-237334821-C-G is Benign according to our data. Variant chr2-237334821-C-G is described in ClinVar as Benign. ClinVar VariationId is 95014.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.943 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL6A3	NM_004369.4 link	c.9034G>C	p.Ala3012Pro	missense_variant	Exon 41 of 44	ENST00000295550.9	NP_004360.2	P12111-1D9ZGF2Q8N4Z1Q63HQ4
COL6A3	NM_057167.4 link	c.8416G>C	p.Ala2806Pro	missense_variant	Exon 40 of 43		NP_476508.2	P12111-2Q8N4Z1Q63HQ4
COL6A3	NM_057166.5 link	c.7213G>C	p.Ala2405Pro	missense_variant	Exon 38 of 41		NP_476507.3	P12111-4B7ZW00

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL6A3	ENST00000295550.9 link	c.9034G>C	p.Ala3012Pro	missense_variant	Exon 41 of 44	1	NM_004369.4	ENSP00000295550.4		P12111-1

Frequencies

GnomAD3 genomes

AF:

0.814

AC:

123868

AN:

152090

Hom.:

51067

Cov.:

show subpopulations

Gnomad AFR

AF:

0.951

Gnomad AMI

AF:

0.874

Gnomad AMR

AF:

0.714

Gnomad ASJ

AF:

0.864

Gnomad EAS

AF:

0.722

Gnomad SAS

AF:

0.728

Gnomad FIN

AF:

0.806

Gnomad MID

AF:

0.854

Gnomad NFE

AF:

0.765

Gnomad OTH

AF:

0.815

GnomAD2 exomes

AF:

0.764

AC:

192082

AN:

251394

AF XY:

0.764

show subpopulations

Gnomad AFR exome

AF:

0.954

Gnomad AMR exome

AF:

0.653

Gnomad ASJ exome

AF:

0.857

Gnomad EAS exome

AF:

0.708

Gnomad FIN exome

AF:

0.803

Gnomad NFE exome

AF:

0.771

Gnomad OTH exome

AF:

0.782

GnomAD4 exome

AF:

0.765

AC:

1118816

AN:

1461824

Hom.:

429690

Cov.:

AF XY:

0.764

AC XY:

555611

AN XY:

727222

show subpopulations

African (AFR)

AF:

0.960

AC:

32124

AN:

33478

American (AMR)

AF:

0.663

AC:

29657

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.855

AC:

22335

AN:

26136

East Asian (EAS)

AF:

0.732

AC:

29055

AN:

39700

South Asian (SAS)

AF:

0.733

AC:

63218

AN:

86258

European-Finnish (FIN)

AF:

0.798

AC:

42603

AN:

53418

Middle Eastern (MID)

AF:

0.855

AC:

4926

AN:

5764

European-Non Finnish (NFE)

AF:

0.762

AC:

847258

AN:

1111956

Other (OTH)

AF:

0.789

AC:

47640

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

15762

31524

47286

63048

78810

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

20396

40792

61188

81584

101980

<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:

0.815

AC:

123990

AN:

152208

Hom.:

51127

Cov.:

AF XY:

0.811

AC XY:

60375

AN XY:

74426

show subpopulations

African (AFR)

AF:

0.951

AC:

39513

AN:

41542

American (AMR)

AF:

0.715

AC:

10932

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.864

AC:

2997

AN:

3470

East Asian (EAS)

AF:

0.721

AC:

3727

AN:

5166

South Asian (SAS)

AF:

0.728

AC:

3510

AN:

4822

European-Finnish (FIN)

AF:

0.806

AC:

8539

AN:

10596

Middle Eastern (MID)

AF:

0.854

AC:

251

AN:

294

European-Non Finnish (NFE)

AF:

0.765

AC:

52002

AN:

68000

Other (OTH)

AF:

0.816

AC:

1724

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1139

2278

3418

4557

5696

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

872

1744

2616

3488

4360

<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:

0.774

Hom.:

31555

Bravo

AF:

0.816

TwinsUK

AF:

0.770

AC:

2854

ALSPAC

AF:

0.761

AC:

2931

ESP6500AA

AF:

0.946

AC:

4167

ESP6500EA

AF:

0.778

AC:

6694

ExAC

AF:

0.773

AC:

93813

Asia WGS

AF:

0.755

AC:

2631

AN:

3478

EpiCase

AF:

0.781

EpiControl

AF:

0.780

ClinVar

Significance: Benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:9

Jan 04, 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. -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

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

- -

Jul 31, 2012

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 31, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 94% 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: 87. Only high quality variants are reported. -

Bethlem myopathy 1A

Benign:2

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 30, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dystonia 27

Benign:1

Jul 30, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Collagen 6-related myopathy

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Ullrich congenital muscular dystrophy 1A

Benign:1

Jul 30, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.038

BayesDel_addAF

Benign

-0.72

BayesDel_noAF

Benign

-0.67

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.11

.;T;.;T;.

Eigen

Benign

-0.83

Eigen_PC

Benign

-0.52

FATHMM_MKL

Benign

0.051

LIST_S2

Benign

0.082

T;T;T;T;.

MetaRNN

Benign

7.7e-7

T;T;T;T;T

MetaSVM

Benign

-0.94

MutationAssessor

Benign

-2.3

.;N;.;.;.

PhyloP100

5.6

PrimateAI

Benign

0.34

PROVEAN

Benign

2.6

N;N;N;.;N

REVEL

Benign

0.095

Sift

Benign

1.0

T;T;T;.;T

Sift4G

Benign

1.0

T;T;T;T;T

Polyphen

0.0

B;B;.;.;B

Vest4

0.14

MPC

0.19

ClinPred

0.018

GERP RS

5.3

Varity_R

0.12

gMVP

0.38

Mutation Taster

=98/2

polymorphism (auto)

(source)

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

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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