rs2646258

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_004369.4(COL6A3):c.7512C>T(p.Asn2504Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.104 in 1,614,070 control chromosomes in the GnomAD database, including 9,107 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.11 ( 904 hom., cov: 32)

Exomes 𝑓: 0.10 ( 8203 hom. )

Consequence

COL6A3
NM_004369.4 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -3.08

Publications

13 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.87).

BP6

Variant 2-237344506-G-A is Benign according to our data. Variant chr2-237344506-G-A is described in ClinVar as Benign. ClinVar VariationId is 94989.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-3.08 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.156 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
COL6A3	NM_004369.4 link	c.7512C>T	p.Asn2504Asn	synonymous_variant	Exon 36 of 44	ENST00000295550.9	NP_004360.2
COL6A3	NM_057167.4 link	c.6894C>T	p.Asn2298Asn	synonymous_variant	Exon 35 of 43		NP_476508.2
COL6A3	NM_057166.5 link	c.5691C>T	p.Asn1897Asn	synonymous_variant	Exon 33 of 41		NP_476507.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL6A3	ENST00000295550.9 link	c.7512C>T	p.Asn2504Asn	synonymous_variant	Exon 36 of 44	1	NM_004369.4	ENSP00000295550.4

Frequencies

GnomAD3 genomes

AF:

0.106

AC:

16132

AN:

152098

Hom.:

904

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0948

Gnomad AMI

AF:

0.0888

Gnomad AMR

AF:

0.161

Gnomad ASJ

AF:

0.131

Gnomad EAS

AF:

0.0494

Gnomad SAS

AF:

0.118

Gnomad FIN

AF:

0.111

Gnomad MID

AF:

0.180

Gnomad NFE

AF:

0.102

Gnomad OTH

AF:

0.118

GnomAD2 exomes

AF:

0.113

AC:

28379

AN:

251384

AF XY:

0.112

show subpopulations

Gnomad AFR exome

AF:

0.0941

Gnomad AMR exome

AF:

0.170

Gnomad ASJ exome

AF:

0.127

Gnomad EAS exome

AF:

0.0472

Gnomad FIN exome

AF:

0.113

Gnomad NFE exome

AF:

0.105

Gnomad OTH exome

AF:

0.114

GnomAD4 exome

AF:

0.104

AC:

152269

AN:

1461854

Hom.:

8203

Cov.:

AF XY:

0.105

AC XY:

76074

AN XY:

727232

show subpopulations

African (AFR)

AF:

0.0957

AC:

3203

AN:

33478

American (AMR)

AF:

0.171

AC:

7631

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.121

AC:

3172

AN:

26136

East Asian (EAS)

AF:

0.0533

AC:

2117

AN:

39700

South Asian (SAS)

AF:

0.119

AC:

10306

AN:

86258

European-Finnish (FIN)

AF:

0.110

AC:

5853

AN:

53418

Middle Eastern (MID)

AF:

0.145

AC:

837

AN:

5768

European-Non Finnish (NFE)

AF:

0.102

AC:

112946

AN:

1111976

Other (OTH)

AF:

0.103

AC:

6204

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

9048

18096

27144

36192

45240

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4188

8376

12564

16752

20940

<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:

0.106

AC:

16138

AN:

152216

Hom.:

904

Cov.:

AF XY:

0.109

AC XY:

8082

AN XY:

74410

show subpopulations

African (AFR)

AF:

0.0947

AC:

3932

AN:

41538

American (AMR)

AF:

0.162

AC:

2471

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.131

AC:

455

AN:

3470

East Asian (EAS)

AF:

0.0493

AC:

255

AN:

5170

South Asian (SAS)

AF:

0.117

AC:

564

AN:

4814

European-Finnish (FIN)

AF:

0.111

AC:

1174

AN:

10590

Middle Eastern (MID)

AF:

0.170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.102

AC:

6910

AN:

68020

Other (OTH)

AF:

0.116

AC:

246

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

716

1432

2148

2864

3580

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

174

348

522

696

870

<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:

0.104

Hom.:

553

Bravo

AF:

0.108

Asia WGS

AF:

0.0800

AC:

279

AN:

3478

EpiCase

AF:

0.110

EpiControl

AF:

0.107

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jul 31, 2012

Eurofins Ntd Llc (ga)

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

- -

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 38% 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: 35. Only high quality variants are reported. -

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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. -

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jun 22, 2021

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Mar 03, 2015

GeneDx

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

- -

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. -

Bethlem myopathy 1A

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

0.043

(source)

DANN

Benign

0.41

PhyloP100

-3.1

PromoterAI

-0.0012

Neutral

(source)

Mutation Taster

=85/15

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