rs148029276

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM1

The NM_001849.4(COL6A2):c.791G>A(p.Arg264His) variant causes a missense change. The variant allele was found at a frequency of 0.000568 in 1,613,370 control chromosomes in the GnomAD database, including 3 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R264C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00051 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00057 ( 3 hom. )

Consequence

COL6A2
NM_001849.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:9B:1

Conservation

PhyloP100: 6.15

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 Uncertain_significance. Variant got 2 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 3 uncertain in NM_001849.4

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
COL6A2	NM_001849.4 linkuse as main transcript	c.791G>A	p.Arg264His	missense_variant	5/28	ENST00000300527.9
COL6A2	NM_058174.3 linkuse as main transcript	c.791G>A	p.Arg264His	missense_variant	5/28	ENST00000397763.6
COL6A2	NM_058175.3 linkuse as main transcript	c.791G>A	p.Arg264His	missense_variant	5/28

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL6A2	ENST00000300527.9 linkuse as main transcript	c.791G>A	p.Arg264His	missense_variant	5/28	1	NM_001849.4	P1	P12110-1
COL6A2	ENST00000397763.6 linkuse as main transcript	c.791G>A	p.Arg264His	missense_variant	5/28	5	NM_058174.3		P12110-2
COL6A2	ENST00000409416.6 linkuse as main transcript	c.791G>A	p.Arg264His	missense_variant	4/27	5			P12110-3
COL6A2	ENST00000485591.1 linkuse as main transcript	n.447G>A		non_coding_transcript_exon_variant	1/7	3

Frequencies

GnomAD3 genomes

AF:

0.000513

AC:

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.000283

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000897

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000442

AC:

111

AN:

251280

Hom.:

AF XY:

0.000456

AC XY:

AN XY:

135898

show subpopulations

Gnomad AFR exome

AF:

0.000246

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.000392

Gnomad FIN exome

AF:

0.000323

Gnomad NFE exome

AF:

0.000748

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000575

AC:

840

AN:

1461080

Hom.:

Cov.:

AF XY:

0.000585

AC XY:

425

AN XY:

726892

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000614

Gnomad4 FIN exome

AF:

0.000453

Gnomad4 NFE exome

AF:

0.000669

Gnomad4 OTH exome

AF:

0.000199

GnomAD4 genome

AF:

0.000506

AC:

AN:

152290

Hom.:

Cov.:

AF XY:

0.000564

AC XY:

AN XY:

74456

show subpopulations

Gnomad4 AFR

AF:

0.000241

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000283

Gnomad4 NFE

AF:

0.000897

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000734

Hom.:

Bravo

AF:

0.000450

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00105

AC:

ExAC

AF:

0.000420

AC:

EpiCase

AF:

0.000763

EpiControl

AF:

0.000415

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:9Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:7

Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 21, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 14, 2023	Reported as a heterozygous variant of uncertain significance in individuals with suspected Limb-Girdle Muscular Dystrophy in published literature (Nallamilli et al., 2018); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 30564623) -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 23, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 13, 2018	- -
Uncertain significance, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2017	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Myosclerosis

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Collagen 6-related myopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Bethlem myopathy 1A

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Nov 27, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Benign

0.011

BayesDel_noAF

Pathogenic

0.21

Cadd

Pathogenic

Dann

Uncertain

0.99

DEOGEN2

Uncertain

0.47

T;.;.;.

Eigen

Uncertain

0.45

Eigen_PC

Uncertain

0.46

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.91

D;D;.;D

M_CAP

Pathogenic

0.46

MetaRNN

Uncertain

0.55

D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Benign

1.2

L;L;L;L

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Uncertain

0.75

PROVEAN

Benign

-1.5

N;N;N;N

REVEL

Pathogenic

0.74

Sift

Benign

0.10

T;T;T;T

Sift4G

Benign

0.11

T;T;T;T

Polyphen

1.0

D;P;P;P

Vest4

0.68

MVP

1.0

MPC

0.67

ClinPred

0.17

GERP RS

4.5

Varity_R

0.19

gMVP

0.50

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