21-46119046-G-A

Position:

chr21-46119046-G-A

Variant summary

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

The NM_001849.4(COL6A2):c.1196G>A(p.Ser399Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.802 in 1,611,660 control chromosomes in the GnomAD database, including 524,735 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.74 ( 43296 hom., cov: 35)

Exomes 𝑓: 0.81 ( 481439 hom. )

Consequence

COL6A2
NM_001849.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: 0.444

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=1.8526694E-6).

BP6

Variant 21-46119046-G-A is Benign according to our data. Variant chr21-46119046-G-A is described in ClinVar as [Benign]. Clinvar id is 93903.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46119046-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.859 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL6A2	NM_001849.4 linkuse as main transcript	c.1196G>A	p.Ser399Asn	missense_variant	14/28	ENST00000300527.9	NP_001840.3	P12110-1A0A384MDP3
COL6A2	NM_058174.3 linkuse as main transcript	c.1196G>A	p.Ser399Asn	missense_variant	14/28		NP_478054.2	P12110-2
COL6A2	NM_058175.3 linkuse as main transcript	c.1196G>A	p.Ser399Asn	missense_variant	14/28		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.1196G>A	p.Ser399Asn	missense_variant	14/28	1	NM_001849.4	ENSP00000300527.4	P12110-1
COL6A2	ENST00000397763.6 linkuse as main transcript	c.1196G>A	p.Ser399Asn	missense_variant	14/28	5		ENSP00000380870.1	P12110-2
COL6A2	ENST00000409416.6 linkuse as main transcript	c.1196G>A	p.Ser399Asn	missense_variant	13/27	5		ENSP00000387115.1	P12110-3

Frequencies

GnomAD3 genomes

AF:

0.742

AC:

112821

AN:

151998

Hom.:

43270

Cov.:

show subpopulations

Gnomad AFR

AF:

0.539

Gnomad AMI

AF:

0.845

Gnomad AMR

AF:

0.856

Gnomad ASJ

AF:

0.794

Gnomad EAS

AF:

0.879

Gnomad SAS

AF:

0.582

Gnomad FIN

AF:

0.799

Gnomad MID

AF:

0.753

Gnomad NFE

AF:

0.827

Gnomad OTH

AF:

0.796

GnomAD3 exomes

AF:

0.785

AC:

195635

AN:

249272

Hom.:

78442

AF XY:

0.776

AC XY:

104951

AN XY:

135318

show subpopulations

Gnomad AFR exome

AF:

0.532

Gnomad AMR exome

AF:

0.897

Gnomad ASJ exome

AF:

0.789

Gnomad EAS exome

AF:

0.866

Gnomad SAS exome

AF:

0.581

Gnomad FIN exome

AF:

0.807

Gnomad NFE exome

AF:

0.823

Gnomad OTH exome

AF:

0.809

GnomAD4 exome

AF:

0.808

AC:

1179688

AN:

1459544

Hom.:

481439

Cov.:

AF XY:

0.802

AC XY:

582009

AN XY:

726124

show subpopulations

Gnomad4 AFR exome

AF:

0.522

Gnomad4 AMR exome

AF:

0.894

Gnomad4 ASJ exome

AF:

0.798

Gnomad4 EAS exome

AF:

0.910

Gnomad4 SAS exome

AF:

0.583

Gnomad4 FIN exome

AF:

0.805

Gnomad4 NFE exome

AF:

0.829

Gnomad4 OTH exome

AF:

0.795

GnomAD4 genome

AF:

0.742

AC:

112891

AN:

152116

Hom.:

43296

Cov.:

AF XY:

0.742

AC XY:

55231

AN XY:

74386

show subpopulations

Gnomad4 AFR

AF:

0.539

Gnomad4 AMR

AF:

0.856

Gnomad4 ASJ

AF:

0.794

Gnomad4 EAS

AF:

0.880

Gnomad4 SAS

AF:

0.581

Gnomad4 FIN

AF:

0.799

Gnomad4 NFE

AF:

0.827

Gnomad4 OTH

AF:

0.792

Alfa

AF:

0.804

Hom.:

91224

Bravo

AF:

0.743

TwinsUK

AF:

0.831

AC:

3082

ALSPAC

AF:

0.832

AC:

3206

ESP6500AA

AF:

0.537

AC:

2362

ESP6500EA

AF:

0.828

AC:

7118

ExAC

AF:

0.772

AC:

93284

Asia WGS

AF:

0.725

AC:

2522

AN:

3478

EpiCase

AF:

0.821

EpiControl

AF:

0.813

ClinVar

Significance: Benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 31, 2012	- -
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, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 05, 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. -

Myosclerosis

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 30, 2021	- -

Bethlem myopathy 1A

Benign:2

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

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

- -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.43

CADD

Benign

1.9

DANN

Benign

0.84

DEOGEN2

Benign

0.13

T;.;.;.

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.016

LIST_S2

Benign

0.17

T;T;.;T

MetaRNN

Benign

0.0000019

T;T;T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.71

N;N;N;N

PrimateAI

Uncertain

0.49

PROVEAN

Benign

0.76

N;N;N;N

REVEL

Benign

0.15

Sift

Benign

0.90

T;T;T;T

Sift4G

Benign

0.52

T;T;T;T

Polyphen

0.0

B;B;B;B

Vest4

0.052

MPC

0.13

ClinPred

0.00024

GERP RS

0.70

Varity_R

0.032

gMVP

0.073

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