21-46112542-G-A

Position:

chr21-46112542-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001849.4(COL6A2):c.679G>A(p.Asp227Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0257 in 1,611,910 control chromosomes in the GnomAD database, including 622 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D227E) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.026 ( 69 hom., cov: 32)

Exomes 𝑓: 0.026 ( 553 hom. )

Consequence

COL6A2
NM_001849.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 1.04

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=0.003347218).

BP6

Variant 21-46112542-G-A is Benign according to our data. Variant chr21-46112542-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 93956.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46112542-G-A is described in Lovd as [Benign]. Variant chr21-46112542-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0263 (3994/152068) while in subpopulation AFR AF= 0.0319 (1323/41468). AF 95% confidence interval is 0.0305. There are 69 homozygotes in gnomad4. There are 1881 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 69 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
COL6A2	NM_001849.4 linkuse as main transcript	c.679G>A	p.Asp227Asn	missense_variant	3/28	ENST00000300527.9
COL6A2	NM_058174.3 linkuse as main transcript	c.679G>A	p.Asp227Asn	missense_variant	3/28	ENST00000397763.6
COL6A2	NM_058175.3 linkuse as main transcript	c.679G>A	p.Asp227Asn	missense_variant	3/28

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL6A2	ENST00000300527.9 linkuse as main transcript	c.679G>A	p.Asp227Asn	missense_variant	3/28	1	NM_001849.4	P1	P12110-1
COL6A2	ENST00000397763.6 linkuse as main transcript	c.679G>A	p.Asp227Asn	missense_variant	3/28	5	NM_058174.3		P12110-2
COL6A2	ENST00000409416.6 linkuse as main transcript	c.679G>A	p.Asp227Asn	missense_variant	2/27	5			P12110-3
COL6A2	ENST00000460886.1 linkuse as main transcript	n.125G>A		non_coding_transcript_exon_variant	1/2	2

Frequencies

GnomAD3 genomes

AF:

0.0262

AC:

3988

AN:

151950

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0319

Gnomad AMI

AF:

0.0175

Gnomad AMR

AF:

0.0305

Gnomad ASJ

AF:

0.0216

Gnomad EAS

AF:

0.000194

Gnomad SAS

AF:

0.0141

Gnomad FIN

AF:

0.00509

Gnomad MID

AF:

0.0348

Gnomad NFE

AF:

0.0279

Gnomad OTH

AF:

0.0389

GnomAD3 exomes

AF:

0.0212

AC:

5195

AN:

244682

Hom.:

AF XY:

0.0212

AC XY:

2841

AN XY:

133724

show subpopulations

Gnomad AFR exome

AF:

0.0305

Gnomad AMR exome

AF:

0.0250

Gnomad ASJ exome

AF:

0.0211

Gnomad EAS exome

AF:

0.000165

Gnomad SAS exome

AF:

0.0143

Gnomad FIN exome

AF:

0.00581

Gnomad NFE exome

AF:

0.0269

Gnomad OTH exome

AF:

0.0269

GnomAD4 exome

AF:

0.0257

AC:

37489

AN:

1459842

Hom.:

553

Cov.:

AF XY:

0.0254

AC XY:

18454

AN XY:

726296

show subpopulations

Gnomad4 AFR exome

AF:

0.0294

Gnomad4 AMR exome

AF:

0.0248

Gnomad4 ASJ exome

AF:

0.0213

Gnomad4 EAS exome

AF:

0.000151

Gnomad4 SAS exome

AF:

0.0150

Gnomad4 FIN exome

AF:

0.00701

Gnomad4 NFE exome

AF:

0.0284

Gnomad4 OTH exome

AF:

0.0245

GnomAD4 genome

AF:

0.0263

AC:

3994

AN:

152068

Hom.:

Cov.:

AF XY:

0.0253

AC XY:

1881

AN XY:

74342

show subpopulations

Gnomad4 AFR

AF:

0.0319

Gnomad4 AMR

AF:

0.0305

Gnomad4 ASJ

AF:

0.0216

Gnomad4 EAS

AF:

0.000194

Gnomad4 SAS

AF:

0.0142

Gnomad4 FIN

AF:

0.00509

Gnomad4 NFE

AF:

0.0279

Gnomad4 OTH

AF:

0.0385

Alfa

AF:

0.0266

Hom.:

Bravo

AF:

0.0276

TwinsUK

AF:

0.0237

AC:

ALSPAC

AF:

0.0257

AC:

ESP6500AA

AF:

0.0266

AC:

117

ESP6500EA

AF:

0.0274

AC:

235

ExAC

AF:

0.0205

AC:

2492

Asia WGS

AF:

0.00808

AC:

AN:

3478

EpiCase

AF:

0.0288

EpiControl

AF:

0.0298

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 26, 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. -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 06, 2012	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 06, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Myosclerosis

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Bethlem myopathy 1A

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Collagen 6-related myopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.43

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.20

T;.;.;.

Eigen

Benign

-0.54

Eigen_PC

Benign

-0.43

FATHMM_MKL

Benign

0.35

LIST_S2

Benign

0.79

T;T;.;T

MetaRNN

Benign

0.0033

T;T;T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

0.55

N;N;N;N

MutationTaster

Benign

0.97

N;N;N;N;N

PrimateAI

Benign

0.40

PROVEAN

Benign

-1.3

N;N;N;N

REVEL

Benign

0.13

Sift

Benign

0.51

T;T;T;T

Sift4G

Benign

0.69

T;T;T;T

Polyphen

0.42

B;B;B;B

Vest4

0.35

MPC

0.13

ClinPred

0.0055

GERP RS

3.2

Varity_R

0.11

gMVP

0.61

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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