dbSNP rs13052956: COL6A2:p.Ala698Ala (chr21-46125909-G-A) – ACMG Classification: Benign (-21 pts)

Variant summary

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

The NM_001849.4(COL6A2):c.2094G>A(p.Ala698Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.483 in 1,612,530 control chromosomes in the GnomAD database, including 193,833 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.44 ( 16251 hom., cov: 32)

Exomes 𝑓: 0.49 ( 177582 hom. )

Consequence

COL6A2
NM_001849.4 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -5.32

Publications

20 publications found

Variant links:

Genes affected

COL6A2 (HGNC:2212): (collagen type VI alpha 2 chain) This gene encodes one of the three alpha chains of type VI collagen, a beaded filament collagen found in most connective tissues. The product of this gene contains several domains similar to von Willebrand Factor type A domains. 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 this gene are associated with Bethlem myopathy and Ullrich scleroatonic muscular dystrophy. Three transcript variants have been identified for this gene. [provided by RefSeq, Jul 2008]

COL6A2 Gene-Disease associations (from GenCC):

collagen 6-related myopathy
Inheritance: AD, AR Classification: DEFINITIVE Submitted by: ClinGen
Ullrich congenital muscular dystrophy 1B
Inheritance: AR, AD Classification: DEFINITIVE Submitted by: G2P
Bethlem myopathy 1A
Inheritance: AD, AR Classification: STRONG Submitted by: Genomics England PanelApp
Ullrich congenital muscular dystrophy 1A
Inheritance: AD, AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
Bethlem myopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Ullrich congenital muscular dystrophy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
myosclerosis
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

COL6A2 links:

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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=-0.69).

BP6

Variant 21-46125909-G-A is Benign according to our data. Variant chr21-46125909-G-A is described in ClinVar as Benign. ClinVar VariationId is 93930.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-5.32 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.566 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001849.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
COL6A2	NM_001849.4	MANE Select	c.2094G>A	p.Ala698Ala	synonymous	Exon 26 of 28	NP_001840.3
COL6A2	NM_058174.3	MANE Plus Clinical	c.2094G>A	p.Ala698Ala	synonymous	Exon 26 of 28	NP_478054.2
COL6A2	NM_058175.3		c.2094G>A	p.Ala698Ala	synonymous	Exon 26 of 28	NP_478055.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
COL6A2	ENST00000300527.9	TSL:1 MANE Select	c.2094G>A	p.Ala698Ala	synonymous	Exon 26 of 28	ENSP00000300527.4
COL6A2	ENST00000397763.6	TSL:5 MANE Plus Clinical	c.2094G>A	p.Ala698Ala	synonymous	Exon 26 of 28	ENSP00000380870.1
COL6A2	ENST00000409416.6	TSL:5	c.2094G>A	p.Ala698Ala	synonymous	Exon 25 of 27	ENSP00000387115.1

Frequencies

GnomAD3 genomes

AF:

0.444

AC:

67404

AN:

151684

Hom.:

16236

Cov.:

show subpopulations

Gnomad AFR

AF:

0.250

Gnomad AMI

AF:

0.581

Gnomad AMR

AF:

0.576

Gnomad ASJ

AF:

0.524

Gnomad EAS

AF:

0.450

Gnomad SAS

AF:

0.332

Gnomad FIN

AF:

0.614

Gnomad MID

AF:

0.424

Gnomad NFE

AF:

0.508

Gnomad OTH

AF:

0.460

GnomAD2 exomes

AF:

0.491

AC:

123082

AN:

250764

AF XY:

0.481

show subpopulations

Gnomad AFR exome

AF:

0.242

Gnomad AMR exome

AF:

0.653

Gnomad ASJ exome

AF:

0.519

Gnomad EAS exome

AF:

0.439

Gnomad FIN exome

AF:

0.620

Gnomad NFE exome

AF:

0.501

Gnomad OTH exome

AF:

0.516

GnomAD4 exome

AF:

0.487

AC:

711760

AN:

1460726

Hom.:

177582

Cov.:

AF XY:

0.483

AC XY:

350674

AN XY:

726710

show subpopulations

African (AFR)

AF:

0.229

AC:

7671

AN:

33478

American (AMR)

AF:

0.644

AC:

28799

AN:

44702

Ashkenazi Jewish (ASJ)

AF:

0.521

AC:

13607

AN:

26132

East Asian (EAS)

AF:

0.433

AC:

17169

AN:

39690

South Asian (SAS)

AF:

0.331

AC:

28556

AN:

86256

European-Finnish (FIN)

AF:

0.612

AC:

32143

AN:

52536

Middle Eastern (MID)

AF:

0.431

AC:

2485

AN:

5766

European-Non Finnish (NFE)

AF:

0.497

AC:

552543

AN:

1111790

Other (OTH)

AF:

0.477

AC:

28787

AN:

60376

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.437

Heterozygous variant carriers

23068

46137

69205

92274

115342

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

15966

31932

47898

63864

79830

<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:

0.444

AC:

67438

AN:

151804

Hom.:

16251

Cov.:

AF XY:

0.450

AC XY:

33328

AN XY:

74118

show subpopulations

African (AFR)

AF:

0.250

AC:

10356

AN:

41428

American (AMR)

AF:

0.576

AC:

8800

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.524

AC:

1815

AN:

3466

East Asian (EAS)

AF:

0.450

AC:

2296

AN:

5104

South Asian (SAS)

AF:

0.332

AC:

1598

AN:

4808

European-Finnish (FIN)

AF:

0.614

AC:

6475

AN:

10538

Middle Eastern (MID)

AF:

0.425

AC:

124

AN:

292

European-Non Finnish (NFE)

AF:

0.508

AC:

34483

AN:

67874

Other (OTH)

AF:

0.456

AC:

962

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

1855

3710

5566

7421

9276

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

610

1220

1830

2440

3050

<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:

0.475

Hom.:

10398

Bravo

AF:

0.436

Asia WGS

AF:

0.402

AC:

1395

AN:

3478

EpiCase

AF:

0.492

EpiControl

AF:

0.489

ClinVar

Significance: Benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Jul 31, 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

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

not provided

Benign:3

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

Sep 13, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Myosclerosis

Benign:2

Jun 14, 2016

Illumina Laboratory Services, Illumina

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

Bethlem myopathy 1A

Benign:2

Feb 03, 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

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.

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 v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.69

CADD

Benign

4.6

(source)

DANN

Benign

0.73

PhyloP100

-5.3

Mutation Taster

=98/2

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.090

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over