rs75120695

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.2351G>A(p.Arg784His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00581 in 1,608,916 control chromosomes in the GnomAD database, including 35 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 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. R784P) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0042 ( 2 hom., cov: 33)

Exomes 𝑓: 0.0060 ( 33 hom. )

Consequence

COL6A2
NM_001849.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: 1.40

Publications

14 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=0.011590838).

BP6

Variant 21-46126166-G-A is Benign according to our data. Variant chr21-46126166-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 93938.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.00597 (8703/1456590) while in subpopulation NFE AF = 0.00716 (7964/1111958). AF 95% confidence interval is 0.00703. There are 33 homozygotes in GnomAdExome4. There are 4242 alleles in the male GnomAdExome4 subpopulation. Median coverage is 38. This position passed quality control check.

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.2351G>A	p.Arg784His	missense_variant	Exon 26 of 28	ENST00000300527.9	NP_001840.3	P12110-1A0A384MDP3
COL6A2	NM_058174.3 link	c.2351G>A	p.Arg784His	missense_variant	Exon 26 of 28		NP_478054.2	P12110-2
COL6A2	NM_058175.3 link	c.2351G>A	p.Arg784His	missense_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.2351G>A	p.Arg784His	missense_variant	Exon 26 of 28	1	NM_001849.4	ENSP00000300527.4	P12110-1
COL6A2	ENST00000397763.6 link	c.2351G>A	p.Arg784His	missense_variant	Exon 26 of 28	5		ENSP00000380870.1	P12110-2
COL6A2	ENST00000409416.6 link	c.2351G>A	p.Arg784His	missense_variant	Exon 25 of 27	5		ENSP00000387115.1	P12110-3

Frequencies

GnomAD3 genomes

AF:

0.00421

AC:

641

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00687

Gnomad ASJ

AF:

0.00317

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.000829

Gnomad FIN

AF:

0.00226

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00625

Gnomad OTH

AF:

0.00526

GnomAD2 exomes

AF:

0.00444

AC:

1096

AN:

246884

AF XY:

0.00441

show subpopulations

Gnomad AFR exome

AF:

0.00124

Gnomad AMR exome

AF:

0.00463

Gnomad ASJ exome

AF:

0.00129

Gnomad EAS exome

AF:

0.0000545

Gnomad FIN exome

AF:

0.00256

Gnomad NFE exome

AF:

0.00704

Gnomad OTH exome

AF:

0.00492

GnomAD4 exome

AF:

0.00597

AC:

8703

AN:

1456590

Hom.:

Cov.:

AF XY:

0.00585

AC XY:

4242

AN XY:

724792

show subpopulations

African (AFR)

AF:

0.000717

AC:

AN:

33478

American (AMR)

AF:

0.00445

AC:

199

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00149

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.00105

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00230

AC:

111

AN:

48244

Middle Eastern (MID)

AF:

0.000867

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00716

AC:

7964

AN:

1111958

Other (OTH)

AF:

0.00447

AC:

270

AN:

60338

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

529

1058

1586

2115

2644

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

298

596

894

1192

1490

<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:

0.00421

AC:

642

AN:

152326

Hom.:

Cov.:

AF XY:

0.00381

AC XY:

284

AN XY:

74480

show subpopulations

African (AFR)

AF:

0.00144

AC:

AN:

41574

American (AMR)

AF:

0.00686

AC:

105

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00317

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5174

South Asian (SAS)

AF:

0.000829

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00226

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00626

AC:

426

AN:

68038

Other (OTH)

AF:

0.00520

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

103

138

172

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.00559

Hom.:

Bravo

AF:

0.00426

TwinsUK

AF:

0.00647

AC:

ALSPAC

AF:

0.00571

AC:

ESP6500AA

AF:

0.00204

AC:

ESP6500EA

AF:

0.00616

AC:

ExAC

AF:

0.00451

AC:

548

Asia WGS

AF:

0.000867

AC:

AN:

3476

EpiCase

AF:

0.00616

EpiControl

AF:

0.00765

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:6

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

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 26, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

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:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

COL6A2: BP4, BS2 -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

May 21, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 20981092, 20729548, 19884007, 15689448, 16935502) -

not specified

Benign:4

Sep 18, 2013

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 25, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

p.Arg784His in exon 26 of COL6A2: This variant is not expected to have clinical significance because it has been identified in 0.7% (445/65546) of European chro mosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.or g; dbSNP rs75120695). Although this variant has been reported in 3 individuals w ith muscular dystrophy or myopathy (Lampe 2005, Foley 2009, Tooley 2010), in at least 2 of these cases a pathogenic COL6A2 variant was identified in cis (on the same copy of the gene) with the p.Arg784His variant. -

PreventionGenetics, part of Exact Sciences

Significance:Likely 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

- -

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

- -

May 28, 2019

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Collagen 6-related myopathy

Benign:1

Mar 06, 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

0.084

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Uncertain

-0.060

CADD

Benign

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.22

T;.;.;.

Eigen

Benign

-0.47

Eigen_PC

Benign

-0.33

FATHMM_MKL

Benign

0.68

LIST_S2

Uncertain

0.87

D;D;.;D

M_CAP

Benign

0.075

MetaRNN

Benign

0.012

T;T;T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.46

N;N;N;N

PhyloP100

1.4

PrimateAI

Benign

0.39

PROVEAN

Benign

-1.9

N;N;N;N

REVEL

Uncertain

0.42

Sift

Benign

0.35

T;T;T;T

Sift4G

Benign

0.57

T;T;T;T

Polyphen

0.049

B;B;B;B

Vest4

0.48

MVP

0.70

MPC

0.17

ClinPred

0.012

GERP RS

2.8

Varity_R

0.081

gMVP

0.60

Mutation Taster

=91/9

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