rs61735831

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_001849.4(COL6A2):c.2600G>A(p.Arg867Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000649 in 1,597,344 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R867W) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0015 ( 2 hom., cov: 34)

Exomes 𝑓: 0.00056 ( 2 hom. )

Consequence

COL6A2
NM_001849.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 1.86

Publications

6 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 -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008332074).

BP6

Variant 21-46132092-G-A is Benign according to our data. Variant chr21-46132092-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 258330.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAd4 at 2 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL6A2	NM_001849.4 link	c.2600G>A	p.Arg867Gln	missense_variant	Exon 28 of 28	ENST00000300527.9	NP_001840.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL6A2	ENST00000300527.9 link	c.2600G>A	p.Arg867Gln	missense_variant	Exon 28 of 28	1	NM_001849.4	ENSP00000300527.4

Frequencies

GnomAD3 genomes

AF:

0.00151

AC:

230

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00432

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000916

Gnomad ASJ

AF:

0.00202

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00186

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000250

Gnomad OTH

AF:

0.00143

GnomAD2 exomes

AF:

0.000932

AC:

201

AN:

215642

AF XY:

0.000927

show subpopulations

Gnomad AFR exome

AF:

0.00490

Gnomad AMR exome

AF:

0.000435

Gnomad ASJ exome

AF:

0.00254

Gnomad EAS exome

AF:

0.000317

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000229

Gnomad OTH exome

AF:

0.000549

GnomAD4 exome

AF:

0.000556

AC:

804

AN:

1445020

Hom.:

Cov.:

AF XY:

0.000619

AC XY:

445

AN XY:

718498

show subpopulations

African (AFR)

AF:

0.00462

AC:

153

AN:

33092

American (AMR)

AF:

0.000835

AC:

AN:

43132

Ashkenazi Jewish (ASJ)

AF:

0.00185

AC:

AN:

25882

East Asian (EAS)

AF:

0.000181

AC:

AN:

38726

South Asian (SAS)

AF:

0.00229

AC:

194

AN:

84628

European-Finnish (FIN)

AF:

0.0000211

AC:

AN:

47466

Middle Eastern (MID)

AF:

0.00174

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

0.000272

AC:

301

AN:

1106608

Other (OTH)

AF:

0.000904

AC:

AN:

59730

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

134

200

267

334

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.00152

AC:

232

AN:

152324

Hom.:

Cov.:

AF XY:

0.00152

AC XY:

113

AN XY:

74482

show subpopulations

African (AFR)

AF:

0.00435

AC:

181

AN:

41580

American (AMR)

AF:

0.000914

AC:

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.00202

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5170

South Asian (SAS)

AF:

0.00186

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000250

AC:

AN:

68016

Other (OTH)

AF:

0.00142

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.000569

Hom.:

Bravo

AF:

0.00155

ESP6500AA

AF:

0.00388

AC:

ESP6500EA

AF:

0.000350

AC:

ExAC

AF:

0.000854

AC:

102

Asia WGS

AF:

0.00462

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 09, 2015

Eurofins Ntd Llc (ga)

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 25, 2024

Athena Diagnostics

Significance:Likely 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. -

Bethlem myopathy 1A

Benign:1

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Sep 17, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 24036952, 18825676) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.093

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.25

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.20

Eigen

Benign

-0.61

Eigen_PC

Benign

-0.71

FATHMM_MKL

Benign

0.15

LIST_S2

Uncertain

0.88

M_CAP

Uncertain

0.16

MetaRNN

Benign

0.0083

MetaSVM

Benign

-0.59

MutationAssessor

Benign

1.7

PhyloP100

1.9

PrimateAI

Benign

0.44

PROVEAN

Benign

-0.69

REVEL

Benign

0.22

Sift

Benign

0.54

Sift4G

Benign

0.53

Polyphen

0.74

Vest4

0.39

MVP

0.89

MPC

0.62

ClinPred

0.0056

GERP RS

3.3

Varity_R

0.069

gMVP

0.50

Mutation Taster

=94/6

polymorphism

(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