rs35881321

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001849.4(COL6A2):c.679G>A(p.Asp227Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0257 in 1,611,910 control chromosomes in the GnomAD database, including 622 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 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. D227E) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.026 ( 69 hom., cov: 32)

Exomes 𝑓: 0.026 ( 553 hom. )

Consequence

COL6A2
NM_001849.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: 1.04

Publications

16 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.003347218).

BP6

Variant 21-46112542-G-A is Benign according to our data. Variant chr21-46112542-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 93956.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0263 (3994/152068) while in subpopulation AFR AF = 0.0319 (1323/41468). AF 95% confidence interval is 0.0305. There are 69 homozygotes in GnomAd4. There are 1881 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 69 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
COL6A2	NM_001849.4 link	c.679G>A	p.Asp227Asn	missense_variant	Exon 3 of 28	ENST00000300527.9	NP_001840.3
COL6A2	NM_058174.3 link	c.679G>A	p.Asp227Asn	missense_variant	Exon 3 of 28	ENST00000397763.6	NP_478054.2
COL6A2	NM_058175.3 link	c.679G>A	p.Asp227Asn	missense_variant	Exon 3 of 28		NP_478055.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL6A2	ENST00000300527.9 link	c.679G>A	p.Asp227Asn	missense_variant	Exon 3 of 28	1	NM_001849.4	ENSP00000300527.4
COL6A2	ENST00000397763.6 link	c.679G>A	p.Asp227Asn	missense_variant	Exon 3 of 28	5	NM_058174.3	ENSP00000380870.1

Frequencies

GnomAD3 genomes

AF:

0.0262

AC:

3988

AN:

151950

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0319

Gnomad AMI

AF:

0.0175

Gnomad AMR

AF:

0.0305

Gnomad ASJ

AF:

0.0216

Gnomad EAS

AF:

0.000194

Gnomad SAS

AF:

0.0141

Gnomad FIN

AF:

0.00509

Gnomad MID

AF:

0.0348

Gnomad NFE

AF:

0.0279

Gnomad OTH

AF:

0.0389

GnomAD2 exomes

AF:

0.0212

AC:

5195

AN:

244682

AF XY:

0.0212

show subpopulations

Gnomad AFR exome

AF:

0.0305

Gnomad AMR exome

AF:

0.0250

Gnomad ASJ exome

AF:

0.0211

Gnomad EAS exome

AF:

0.000165

Gnomad FIN exome

AF:

0.00581

Gnomad NFE exome

AF:

0.0269

Gnomad OTH exome

AF:

0.0269

GnomAD4 exome

AF:

0.0257

AC:

37489

AN:

1459842

Hom.:

553

Cov.:

AF XY:

0.0254

AC XY:

18454

AN XY:

726296

show subpopulations

African (AFR)

AF:

0.0294

AC:

985

AN:

33466

American (AMR)

AF:

0.0248

AC:

1108

AN:

44704

Ashkenazi Jewish (ASJ)

AF:

0.0213

AC:

557

AN:

26118

East Asian (EAS)

AF:

0.000151

AC:

AN:

39660

South Asian (SAS)

AF:

0.0150

AC:

1291

AN:

86234

European-Finnish (FIN)

AF:

0.00701

AC:

362

AN:

51676

Middle Eastern (MID)

AF:

0.0291

AC:

168

AN:

5768

European-Non Finnish (NFE)

AF:

0.0284

AC:

31534

AN:

1111858

Other (OTH)

AF:

0.0245

AC:

1478

AN:

60358

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

2296

4591

6887

9182

11478

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1204

2408

3612

4816

6020

<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:

0.0263

AC:

3994

AN:

152068

Hom.:

Cov.:

AF XY:

0.0253

AC XY:

1881

AN XY:

74342

show subpopulations

African (AFR)

AF:

0.0319

AC:

1323

AN:

41468

American (AMR)

AF:

0.0305

AC:

466

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.0216

AC:

AN:

3468

East Asian (EAS)

AF:

0.000194

AC:

AN:

5154

South Asian (SAS)

AF:

0.0142

AC:

AN:

4804

European-Finnish (FIN)

AF:

0.00509

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.0374

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0279

AC:

1899

AN:

67956

Other (OTH)

AF:

0.0385

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

190

380

569

759

949

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

138

184

230

<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:

0.0265

Hom.:

123

Bravo

AF:

0.0276

TwinsUK

AF:

0.0237

AC:

ALSPAC

AF:

0.0257

AC:

ESP6500AA

AF:

0.0266

AC:

117

ESP6500EA

AF:

0.0274

AC:

235

ExAC

AF:

0.0205

AC:

2492

Asia WGS

AF:

0.00808

AC:

AN:

3478

EpiCase

AF:

0.0288

EpiControl

AF:

0.0298

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

PreventionGenetics, part of Exact Sciences

Significance:Likely 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

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Feb 26, 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. -

Sep 06, 2012

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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. -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:4

Nov 06, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

COL6A2: BP4, BS1, BS2 -

Myosclerosis

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Bethlem myopathy 1A

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.43

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.20

T;.;.;.

Eigen

Benign

-0.54

Eigen_PC

Benign

-0.43

FATHMM_MKL

Benign

0.35

LIST_S2

Benign

0.79

T;T;.;T

MetaRNN

Benign

0.0033

T;T;T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

0.55

N;N;N;N

PhyloP100

1.0

PrimateAI

Benign

0.40

PROVEAN

Benign

-1.3

N;N;N;N

REVEL

Benign

0.13

Sift

Benign

0.51

T;T;T;T

Sift4G

Benign

0.69

T;T;T;T

Polyphen

0.42

B;B;B;B

Vest4

0.35

MPC

0.13

ClinPred

0.0055

GERP RS

3.2

Varity_R

0.11

gMVP

0.61

Mutation Taster

=100/0

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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