rs35548026

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001849.4(COL6A2):c.2803G>A(p.Gly935Arg) variant causes a missense change. The variant allele was found at a frequency of 0.084 in 1,605,536 control chromosomes in the GnomAD database, including 5,894 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 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. G935E) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.080 ( 487 hom., cov: 34)

Exomes 𝑓: 0.084 ( 5407 hom. )

Consequence

COL6A2
NM_001849.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 4.63

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.002195537).

BP6

Variant 21-46132295-G-A is Benign according to our data. Variant chr21-46132295-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 93948.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46132295-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0884 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL6A2	NM_001849.4 linkuse as main transcript	c.2803G>A	p.Gly935Arg	missense_variant	28/28	ENST00000300527.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL6A2	ENST00000300527.9 linkuse as main transcript	c.2803G>A	p.Gly935Arg	missense_variant	28/28	1	NM_001849.4	P1	P12110-1

Frequencies

GnomAD3 genomes

AF:

0.0804

AC:

12233

AN:

152076

Hom.:

487

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0748

Gnomad AMI

AF:

0.113

Gnomad AMR

AF:

0.0925

Gnomad ASJ

AF:

0.0828

Gnomad EAS

AF:

0.0544

Gnomad SAS

AF:

0.0496

Gnomad FIN

AF:

0.0825

Gnomad MID

AF:

0.0601

Gnomad NFE

AF:

0.0843

Gnomad OTH

AF:

0.0903

GnomAD3 exomes

AF:

0.0793

AC:

18809

AN:

237052

Hom.:

758

AF XY:

0.0789

AC XY:

10265

AN XY:

130126

show subpopulations

Gnomad AFR exome

AF:

0.0783

Gnomad AMR exome

AF:

0.0748

Gnomad ASJ exome

AF:

0.0828

Gnomad EAS exome

AF:

0.0602

Gnomad SAS exome

AF:

0.0613

Gnomad FIN exome

AF:

0.0846

Gnomad NFE exome

AF:

0.0879

Gnomad OTH exome

AF:

0.0808

GnomAD4 exome

AF:

0.0844

AC:

122592

AN:

1453342

Hom.:

5407

Cov.:

AF XY:

0.0838

AC XY:

60645

AN XY:

723282

show subpopulations

Gnomad4 AFR exome

AF:

0.0804

Gnomad4 AMR exome

AF:

0.0756

Gnomad4 ASJ exome

AF:

0.0844

Gnomad4 EAS exome

AF:

0.0432

Gnomad4 SAS exome

AF:

0.0613

Gnomad4 FIN exome

AF:

0.0861

Gnomad4 NFE exome

AF:

0.0881

Gnomad4 OTH exome

AF:

0.0813

GnomAD4 genome

AF:

0.0804

AC:

12234

AN:

152194

Hom.:

487

Cov.:

AF XY:

0.0795

AC XY:

5918

AN XY:

74402

show subpopulations

Gnomad4 AFR

AF:

0.0747

Gnomad4 AMR

AF:

0.0924

Gnomad4 ASJ

AF:

0.0828

Gnomad4 EAS

AF:

0.0543

Gnomad4 SAS

AF:

0.0493

Gnomad4 FIN

AF:

0.0825

Gnomad4 NFE

AF:

0.0842

Gnomad4 OTH

AF:

0.0899

Alfa

AF:

0.0827

Hom.:

217

Bravo

AF:

0.0824

TwinsUK

AF:

0.0836

AC:

310

ALSPAC

AF:

0.0815

AC:

314

ESP6500AA

AF:

0.0810

AC:

356

ESP6500EA

AF:

0.0816

AC:

701

ExAC

AF:

0.0783

AC:

9422

Asia WGS

AF:

0.0540

AC:

186

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:8

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 06, 2016	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 29, 2016	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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Myosclerosis

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Glutamate formiminotransferase deficiency

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Collagen 6-related myopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Bethlem myopathy 1A

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Nov 06, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.29

Cadd

Benign

Dann

Benign

0.86

DEOGEN2

Benign

0.34

Eigen

Benign

-0.33

Eigen_PC

Benign

-0.42

FATHMM_MKL

Benign

0.31

LIST_S2

Benign

0.59

MetaRNN

Benign

0.0022

MetaSVM

Benign

-0.74

MutationAssessor

Benign

0.68

MutationTaster

Benign

0.88

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-2.3

REVEL

Benign

0.23

Sift

Benign

0.070

Sift4G

Benign

0.15

Polyphen

0.86

Vest4

0.12

MutPred

0.32

Gain of methylation at G935 (P = 0.0097);

MPC

0.38

ClinPred

0.035

GERP RS

3.3

Varity_R

0.064

gMVP

0.81

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over