chr21-46125909-G-A

Position:

chr21-46125909-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001849.4(COL6A2):c.2094G>A(p.Ala698=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.483 in 1,612,530 control chromosomes in the GnomAD database, including 193,833 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.44 ( 16251 hom., cov: 32)

Exomes 𝑓: 0.49 ( 177582 hom. )

Consequence

COL6A2
NM_001849.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:15

Conservation

PhyloP100: -5.32

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.69).

BP6

Variant 21-46125909-G-A is Benign according to our data. Variant chr21-46125909-G-A is described in ClinVar as [Benign]. Clinvar id is 93930.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46125909-G-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-5.32 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.566 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
COL6A2	NM_001849.4 linkuse as main transcript	c.2094G>A	p.Ala698=	synonymous_variant	26/28	ENST00000300527.9	NP_001840.3
COL6A2	NM_058174.3 linkuse as main transcript	c.2094G>A	p.Ala698=	synonymous_variant	26/28	ENST00000397763.6	NP_478054.2
COL6A2	NM_058175.3 linkuse as main transcript	c.2094G>A	p.Ala698=	synonymous_variant	26/28		NP_478055.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL6A2	ENST00000300527.9 linkuse as main transcript	c.2094G>A	p.Ala698=	synonymous_variant	26/28	1	NM_001849.4	ENSP00000300527	P1	P12110-1
COL6A2	ENST00000397763.6 linkuse as main transcript	c.2094G>A	p.Ala698=	synonymous_variant	26/28	5	NM_058174.3	ENSP00000380870		P12110-2
COL6A2	ENST00000409416.6 linkuse as main transcript	c.2094G>A	p.Ala698=	synonymous_variant	25/27	5		ENSP00000387115		P12110-3
COL6A2	ENST00000413758.1 linkuse as main transcript			downstream_gene_variant		3		ENSP00000395751

Frequencies

GnomAD3 genomes

AF:

0.444

AC:

67404

AN:

151684

Hom.:

16236

Cov.:

show subpopulations

Gnomad AFR

AF:

0.250

Gnomad AMI

AF:

0.581

Gnomad AMR

AF:

0.576

Gnomad ASJ

AF:

0.524

Gnomad EAS

AF:

0.450

Gnomad SAS

AF:

0.332

Gnomad FIN

AF:

0.614

Gnomad MID

AF:

0.424

Gnomad NFE

AF:

0.508

Gnomad OTH

AF:

0.460

GnomAD3 exomes

AF:

0.491

AC:

123082

AN:

250764

Hom.:

31986

AF XY:

0.481

AC XY:

65323

AN XY:

135714

show subpopulations

Gnomad AFR exome

AF:

0.242

Gnomad AMR exome

AF:

0.653

Gnomad ASJ exome

AF:

0.519

Gnomad EAS exome

AF:

0.439

Gnomad SAS exome

AF:

0.327

Gnomad FIN exome

AF:

0.620

Gnomad NFE exome

AF:

0.501

Gnomad OTH exome

AF:

0.516

GnomAD4 exome

AF:

0.487

AC:

711760

AN:

1460726

Hom.:

177582

Cov.:

AF XY:

0.483

AC XY:

350674

AN XY:

726710

show subpopulations

Gnomad4 AFR exome

AF:

0.229

Gnomad4 AMR exome

AF:

0.644

Gnomad4 ASJ exome

AF:

0.521

Gnomad4 EAS exome

AF:

0.433

Gnomad4 SAS exome

AF:

0.331

Gnomad4 FIN exome

AF:

0.612

Gnomad4 NFE exome

AF:

0.497

Gnomad4 OTH exome

AF:

0.477

GnomAD4 genome

AF:

0.444

AC:

67438

AN:

151804

Hom.:

16251

Cov.:

AF XY:

0.450

AC XY:

33328

AN XY:

74118

show subpopulations

Gnomad4 AFR

AF:

0.250

Gnomad4 AMR

AF:

0.576

Gnomad4 ASJ

AF:

0.524

Gnomad4 EAS

AF:

0.450

Gnomad4 SAS

AF:

0.332

Gnomad4 FIN

AF:

0.614

Gnomad4 NFE

AF:

0.508

Gnomad4 OTH

AF:

0.456

Alfa

AF:

0.474

Hom.:

8822

Bravo

AF:

0.436

Asia WGS

AF:

0.402

AC:

1395

AN:

3478

EpiCase

AF:

0.492

EpiControl

AF:

0.489

ClinVar

Significance: Benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

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	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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	- -

not provided

Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 13, 2017	- -

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

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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.69

CADD

Benign

4.6

DANN

Benign

0.73

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.090

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