rs1042917

Positions:

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM5BP4_StrongBP6_Very_StrongBA1

The ENST00000300527.9(COL6A2):c.2039G>A(p.Arg680His) variant causes a missense change. The variant allele was found at a frequency of 0.483 in 1,612,622 control chromosomes in the GnomAD database, including 194,042 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R680C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.45 ( 16357 hom., cov: 32)

Exomes 𝑓: 0.49 ( 177685 hom. )

Consequence

COL6A2
ENST00000300527.9 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:16

Conservation

PhyloP100: 4.95

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 -18 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr21-46125853-CG-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 422287.Status of the report is criteria_provided_single_submitter, 1 stars.

BP4

Computational evidence support a benign effect (MetaRNN=9.4074334E-5).

BP6

Variant 21-46125854-G-A is Benign according to our data. Variant chr21-46125854-G-A is described in ClinVar as [Benign]. Clinvar id is 93929.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46125854-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.567 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
COL6A2	NM_001849.4 linkuse as main transcript	c.2039G>A	p.Arg680His	missense_variant	26/28	ENST00000300527.9	NP_001840.3
COL6A2	NM_058174.3 linkuse as main transcript	c.2039G>A	p.Arg680His	missense_variant	26/28	ENST00000397763.6	NP_478054.2
COL6A2	NM_058175.3 linkuse as main transcript	c.2039G>A	p.Arg680His	missense_variant	26/28		NP_478055.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL6A2	ENST00000300527.9 linkuse as main transcript	c.2039G>A	p.Arg680His	missense_variant	26/28	1	NM_001849.4	ENSP00000300527	P1	P12110-1
COL6A2	ENST00000397763.6 linkuse as main transcript	c.2039G>A	p.Arg680His	missense_variant	26/28	5	NM_058174.3	ENSP00000380870		P12110-2
COL6A2	ENST00000409416.6 linkuse as main transcript	c.2039G>A	p.Arg680His	missense_variant	25/27	5		ENSP00000387115		P12110-3
COL6A2	ENST00000413758.1 linkuse as main transcript	c.710G>A	p.Arg237His	missense_variant	11/11	3		ENSP00000395751

Frequencies

GnomAD3 genomes

AF:

0.445

AC:

67577

AN:

151798

Hom.:

16342

Cov.:

show subpopulations

Gnomad AFR

AF:

0.250

Gnomad AMI

AF:

0.582

Gnomad AMR

AF:

0.576

Gnomad ASJ

AF:

0.524

Gnomad EAS

AF:

0.449

Gnomad SAS

AF:

0.333

Gnomad FIN

AF:

0.617

Gnomad MID

AF:

0.430

Gnomad NFE

AF:

0.509

Gnomad OTH

AF:

0.460

GnomAD3 exomes

AF:

0.492

AC:

123178

AN:

250564

Hom.:

32074

AF XY:

0.482

AC XY:

65422

AN XY:

135706

show subpopulations

Gnomad AFR exome

AF:

0.241

Gnomad AMR exome

AF:

0.653

Gnomad ASJ exome

AF:

0.520

Gnomad EAS exome

AF:

0.440

Gnomad SAS exome

AF:

0.327

Gnomad FIN exome

AF:

0.623

Gnomad NFE exome

AF:

0.502

Gnomad OTH exome

AF:

0.517

GnomAD4 exome

AF:

0.487

AC:

711956

AN:

1460706

Hom.:

177685

Cov.:

AF XY:

0.483

AC XY:

350764

AN XY:

726668

show subpopulations

Gnomad4 AFR exome

AF:

0.229

Gnomad4 AMR exome

AF:

0.644

Gnomad4 ASJ exome

AF:

0.521

Gnomad4 EAS exome

AF:

0.433

Gnomad4 SAS exome

AF:

0.331

Gnomad4 FIN exome

AF:

0.614

Gnomad4 NFE exome

AF:

0.497

Gnomad4 OTH exome

AF:

0.477

GnomAD4 genome

AF:

0.445

AC:

67612

AN:

151916

Hom.:

16357

Cov.:

AF XY:

0.451

AC XY:

33455

AN XY:

74220

show subpopulations

Gnomad4 AFR

AF:

0.250

Gnomad4 AMR

AF:

0.577

Gnomad4 ASJ

AF:

0.524

Gnomad4 EAS

AF:

0.450

Gnomad4 SAS

AF:

0.333

Gnomad4 FIN

AF:

0.617

Gnomad4 NFE

AF:

0.509

Gnomad4 OTH

AF:

0.455

Alfa

AF:

0.481

Hom.:

36126

Bravo

AF:

0.436

TwinsUK

AF:

0.499

AC:

1851

ALSPAC

AF:

0.516

AC:

1987

ESP6500AA

AF:

0.241

AC:

1061

ESP6500EA

AF:

0.501

AC:

4310

ExAC

AF:

0.477

AC:

57872

Asia WGS

AF:

0.402

AC:

1396

AN:

3478

EpiCase

AF:

0.492

EpiControl

AF:

0.489

ClinVar

Significance: Benign

Submissions summary: Benign:16

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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 31, 2012	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Bethlem myopathy 1A

Benign:3

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 30, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 13, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 30389748) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Myosclerosis

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 30, 2021	- -
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

Jan 13, 2018

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

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.19

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.22

T;.;.;.;T

Eigen

Uncertain

0.44

Eigen_PC

Uncertain

0.41

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.80

T;T;.;T;T

MetaRNN

Benign

0.000094

T;T;T;T;T

MetaSVM

Benign

-0.85

MutationAssessor

Benign

1.5

L;L;L;L;.

MutationTaster

Benign

0.000071

P;P;P;P;P

PrimateAI

Benign

0.44

PROVEAN

Benign

-0.94

N;N;N;N;N

REVEL

Benign

0.28

Sift

Benign

0.081

T;T;T;D;T

Sift4G

Benign

0.13

T;T;T;T;D

Polyphen

1.0

D;D;D;D;.

Vest4

0.43

MPC

0.68

ClinPred

0.011

GERP RS

4.4

Varity_R

0.22

gMVP

0.72

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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