rs2839114

Variant names:

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.2184G>A(p.Val728Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.366 in 1,612,720 control chromosomes in the GnomAD database, including 112,538 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.33 ( 9456 hom., cov: 32)

Exomes 𝑓: 0.37 ( 103082 hom. )

Consequence

COL6A2
NM_001849.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: 1.86

Publications

23 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:

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=-0.56).

BP6

Variant 21-46125999-G-A is Benign according to our data. Variant chr21-46125999-G-A is described in ClinVar as Benign. ClinVar VariationId is 93936.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=1.86 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.479 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL6A2	NM_001849.4 link	c.2184G>A	p.Val728Val	synonymous_variant	Exon 26 of 28	ENST00000300527.9	NP_001840.3	P12110-1A0A384MDP3
COL6A2	NM_058174.3 link	c.2184G>A	p.Val728Val	synonymous_variant	Exon 26 of 28		NP_478054.2	P12110-2
COL6A2	NM_058175.3 link	c.2184G>A	p.Val728Val	synonymous_variant	Exon 26 of 28		NP_478055.2	P12110-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
COL6A2	ENST00000300527.9 link	c.2184G>A	p.Val728Val	synonymous_variant	Exon 26 of 28	1	NM_001849.4	ENSP00000300527.4	P12110-1
COL6A2	ENST00000397763.6 link	c.2184G>A	p.Val728Val	synonymous_variant	Exon 26 of 28	5		ENSP00000380870.1	P12110-2
COL6A2	ENST00000409416.6 link	c.2184G>A	p.Val728Val	synonymous_variant	Exon 25 of 27	5		ENSP00000387115.1	P12110-3
COL6A2	ENST00000413758.1 link	c.*105G>A		downstream_gene_variant		3		ENSP00000395751.1	H7C0M5

Frequencies

GnomAD3 genomes

AF:

0.329

AC:

49959

AN:

151914

Hom.:

9442

Cov.:

show subpopulations

Gnomad AFR

AF:

0.139

Gnomad AMI

AF:

0.424

Gnomad AMR

AF:

0.487

Gnomad ASJ

AF:

0.374

Gnomad EAS

AF:

0.444

Gnomad SAS

AF:

0.289

Gnomad FIN

AF:

0.461

Gnomad MID

AF:

0.244

Gnomad NFE

AF:

0.379

Gnomad OTH

AF:

0.344

GnomAD2 exomes

AF:

0.389

AC:

97680

AN:

250960

AF XY:

0.380

show subpopulations

Gnomad AFR exome

AF:

0.130

Gnomad AMR exome

AF:

0.592

Gnomad ASJ exome

AF:

0.371

Gnomad EAS exome

AF:

0.434

Gnomad FIN exome

AF:

0.466

Gnomad NFE exome

AF:

0.373

Gnomad OTH exome

AF:

0.403

GnomAD4 exome

AF:

0.369

AC:

539562

AN:

1460686

Hom.:

103082

Cov.:

AF XY:

0.367

AC XY:

266375

AN XY:

726608

show subpopulations

African (AFR)

AF:

0.124

AC:

4147

AN:

33478

American (AMR)

AF:

0.580

AC:

25935

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.378

AC:

9868

AN:

26134

East Asian (EAS)

AF:

0.430

AC:

17079

AN:

39690

South Asian (SAS)

AF:

0.280

AC:

24154

AN:

86254

European-Finnish (FIN)

AF:

0.456

AC:

23934

AN:

52466

Middle Eastern (MID)

AF:

0.278

AC:

1604

AN:

5766

European-Non Finnish (NFE)

AF:

0.370

AC:

410909

AN:

1111796

Other (OTH)

AF:

0.363

AC:

21932

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

23298

46597

69895

93194

116492

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

12924

25848

38772

51696

64620

<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:

0.329

AC:

49979

AN:

152034

Hom.:

9456

Cov.:

AF XY:

0.335

AC XY:

24906

AN XY:

74300

show subpopulations

African (AFR)

AF:

0.138

AC:

5742

AN:

41504

American (AMR)

AF:

0.488

AC:

7458

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.374

AC:

1298

AN:

3470

East Asian (EAS)

AF:

0.445

AC:

2287

AN:

5144

South Asian (SAS)

AF:

0.289

AC:

1393

AN:

4826

European-Finnish (FIN)

AF:

0.461

AC:

4872

AN:

10562

Middle Eastern (MID)

AF:

0.255

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.379

AC:

25747

AN:

67934

Other (OTH)

AF:

0.341

AC:

721

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

1643

3287

4930

6574

8217

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

488

976

1464

1952

2440

<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:

0.348

Hom.:

4986

Bravo

AF:

0.324

Asia WGS

AF:

0.365

AC:

1268

AN:

3478

EpiCase

AF:

0.361

EpiControl

AF:

0.358

ClinVar

Significance: Benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 16, 2017

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. -

Jun 28, 2018

Eurofins Ntd Llc (ga)

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

- -

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

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

- -

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

- -

not provided

Benign:2

Sep 13, 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

- -

Collagen 6-related myopathy

Benign:1

Jan 12, 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 v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.56

CADD

Benign

9.7

(source)

DANN

Benign

0.69

PhyloP100

1.9

Mutation Taster

=93/7

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

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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