chr21-46112362-G-A

Position:

chr21-46112362-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_001849.4(COL6A2):c.499G>A(p.Gly167Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000558 in 1,608,264 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0028 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00033 ( 5 hom. )

Consequence

COL6A2
NM_001849.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 6.62

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 -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009836435).

BP6

Variant 21-46112362-G-A is Benign according to our data. Variant chr21-46112362-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 93954.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAdExome4 at 5 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL6A2	NM_001849.4 linkuse as main transcript	c.499G>A	p.Gly167Ser	missense_variant	3/28	ENST00000300527.9	NP_001840.3	P12110-1A0A384MDP3
COL6A2	NM_058174.3 linkuse as main transcript	c.499G>A	p.Gly167Ser	missense_variant	3/28		NP_478054.2	P12110-2
COL6A2	NM_058175.3 linkuse as main transcript	c.499G>A	p.Gly167Ser	missense_variant	3/28		NP_478055.2	P12110-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
COL6A2	ENST00000300527.9 linkuse as main transcript	c.499G>A	p.Gly167Ser	missense_variant	3/28	1	NM_001849.4	ENSP00000300527.4	P12110-1
COL6A2	ENST00000397763.6 linkuse as main transcript	c.499G>A	p.Gly167Ser	missense_variant	3/28	5		ENSP00000380870.1	P12110-2
COL6A2	ENST00000409416.6 linkuse as main transcript	c.499G>A	p.Gly167Ser	missense_variant	2/27	5		ENSP00000387115.1	P12110-3
COL6A2	ENST00000436769.5 linkuse as main transcript	c.499G>A	p.Gly167Ser	missense_variant	3/3	2		ENSP00000390418.1	C9JH44

Frequencies

GnomAD3 genomes

AF:

0.00276

AC:

419

AN:

152056

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00974

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000590

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000387

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.000714

AC:

168

AN:

235134

Hom.:

AF XY:

0.000532

AC XY:

AN XY:

129766

show subpopulations

Gnomad AFR exome

AF:

0.00969

Gnomad AMR exome

AF:

0.000323

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000454

Gnomad SAS exome

AF:

0.000165

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000670

Gnomad OTH exome

AF:

0.000173

GnomAD4 exome

AF:

0.000329

AC:

479

AN:

1456090

Hom.:

Cov.:

AF XY:

0.000308

AC XY:

223

AN XY:

724080

show subpopulations

Gnomad4 AFR exome

AF:

0.00881

Gnomad4 AMR exome

AF:

0.000426

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00101

Gnomad4 SAS exome

AF:

0.000221

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000649

Gnomad4 OTH exome

AF:

0.000549

GnomAD4 genome

AF:

0.00275

AC:

419

AN:

152174

Hom.:

Cov.:

AF XY:

0.00247

AC XY:

184

AN XY:

74404

show subpopulations

Gnomad4 AFR

AF:

0.00971

Gnomad4 AMR

AF:

0.000589

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000388

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.000474

Alfa

AF:

0.000307

Hom.:

Bravo

AF:

0.00288

ESP6500AA

AF:

0.00657

AC:

ESP6500EA

AF:

0.000120

AC:

ExAC

AF:

0.000939

AC:

112

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000594

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 11, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 02, 2017	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. -

Myosclerosis

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

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

not provided

Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

COL6A2-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 10, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.26

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Uncertain

0.060

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.32

T;.;T;.;.

Eigen

Uncertain

0.59

Eigen_PC

Uncertain

0.57

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

D;D;D;.;D

MetaRNN

Benign

0.0098

T;T;T;T;T

MetaSVM

Uncertain

0.075

MutationAssessor

Uncertain

2.3

M;M;.;M;M

PrimateAI

Uncertain

0.59

PROVEAN

Uncertain

-2.8

D;D;D;D;D

REVEL

Uncertain

0.64

Sift

Benign

0.045

D;D;D;D;D

Sift4G

Uncertain

0.016

D;D;D;D;D

Polyphen

1.0

D;D;.;D;D

Vest4

0.57

MVP

0.91

MPC

0.55

ClinPred

0.015

GERP RS

4.3

Varity_R

0.37

gMVP

0.75

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