rs61735831

Positions:

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM5BP4_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. 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. R867W) has been classified as Likely pathogenic.

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:5

Conservation

PhyloP100: 1.86

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr21-46132091-C-T is described in Lovd as [Likely_pathogenic].

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 [Likely_benign]. Clinvar id is 258330.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAd4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL6A2	NM_001849.4 linkuse as main transcript	c.2600G>A	p.Arg867Gln	missense_variant	28/28	ENST00000300527.9	NP_001840.3	P12110-1A0A384MDP3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL6A2	ENST00000300527.9 linkuse as main transcript	c.2600G>A	p.Arg867Gln	missense_variant	28/28	1	NM_001849.4	ENSP00000300527.4		P12110-1

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

GnomAD3 exomes

AF:

0.000932

AC:

201

AN:

215642

Hom.:

AF XY:

0.000927

AC XY:

110

AN XY:

118690

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 SAS exome

AF:

0.00243

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

Gnomad4 AFR exome

AF:

0.00462

Gnomad4 AMR exome

AF:

0.000835

Gnomad4 ASJ exome

AF:

0.00185

Gnomad4 EAS exome

AF:

0.000181

Gnomad4 SAS exome

AF:

0.00229

Gnomad4 FIN exome

AF:

0.0000211

Gnomad4 NFE exome

AF:

0.000272

Gnomad4 OTH exome

AF:

0.000904

GnomAD4 genome

AF:

0.00152

AC:

232

AN:

152324

Hom.:

Cov.:

AF XY:

0.00152

AC XY:

113

AN XY:

74482

show subpopulations

Gnomad4 AFR

AF:

0.00435

Gnomad4 AMR

AF:

0.000914

Gnomad4 ASJ

AF:

0.00202

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00186

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000250

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.000338

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:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 09, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

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. -

Bethlem myopathy 1A

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 18, 2024

- -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Sep 17, 2020

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

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

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

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