21-46112526-C-T

Position:

chr21-46112526-C-T

Variant summary

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

The NM_001849.4(COL6A2):c.663C>T(p.Pro221Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0851 in 1,607,688 control chromosomes in the GnomAD database, including 6,105 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.097 ( 716 hom., cov: 31)

Exomes 𝑓: 0.084 ( 5389 hom. )

Consequence

COL6A2
NM_001849.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: -4.81

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:

COL6A2 (HGNC:):

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=-0.61).

BP6

Variant 21-46112526-C-T is Benign according to our data. Variant chr21-46112526-C-T is described in ClinVar as [Benign]. Clinvar id is 93955.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46112526-C-T is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-4.81 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.123 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.663C>T	p.Pro221Pro	synonymous_variant	3/28	ENST00000300527.9	NP_001840.3	P12110-1A0A384MDP3
COL6A2	NM_058174.3 linkuse as main transcript	c.663C>T	p.Pro221Pro	synonymous_variant	3/28		NP_478054.2	P12110-2
COL6A2	NM_058175.3 linkuse as main transcript	c.663C>T	p.Pro221Pro	synonymous_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.663C>T	p.Pro221Pro	synonymous_variant	3/28	1	NM_001849.4	ENSP00000300527.4	P12110-1
COL6A2	ENST00000397763.6 linkuse as main transcript	c.663C>T	p.Pro221Pro	synonymous_variant	3/28	5		ENSP00000380870.1	P12110-2
COL6A2	ENST00000409416.6 linkuse as main transcript	c.663C>T	p.Pro221Pro	synonymous_variant	2/27	5		ENSP00000387115.1	P12110-3
COL6A2	ENST00000460886.1 linkuse as main transcript	n.109C>T		non_coding_transcript_exon_variant	1/2	2

Frequencies

GnomAD3 genomes

AF:

0.0968

AC:

14394

AN:

148678

Hom.:

715

Cov.:

show subpopulations

Gnomad AFR

AF:

0.126

Gnomad AMI

AF:

0.113

Gnomad AMR

AF:

0.0938

Gnomad ASJ

AF:

0.0816

Gnomad EAS

AF:

0.127

Gnomad SAS

AF:

0.0538

Gnomad FIN

AF:

0.0934

Gnomad MID

AF:

0.0709

Gnomad NFE

AF:

0.0819

Gnomad OTH

AF:

0.105

GnomAD3 exomes

AF:

0.0854

AC:

20844

AN:

244032

Hom.:

967

AF XY:

0.0835

AC XY:

11133

AN XY:

133376

show subpopulations

Gnomad AFR exome

AF:

0.125

Gnomad AMR exome

AF:

0.0755

Gnomad ASJ exome

AF:

0.0776

Gnomad EAS exome

AF:

0.126

Gnomad SAS exome

AF:

0.0610

Gnomad FIN exome

AF:

0.0924

Gnomad NFE exome

AF:

0.0827

Gnomad OTH exome

AF:

0.0810

GnomAD4 exome

AF:

0.0839

AC:

122364

AN:

1458894

Hom.:

5389

Cov.:

AF XY:

0.0833

AC XY:

60487

AN XY:

725808

show subpopulations

Gnomad4 AFR exome

AF:

0.127

Gnomad4 AMR exome

AF:

0.0770

Gnomad4 ASJ exome

AF:

0.0796

Gnomad4 EAS exome

AF:

0.102

Gnomad4 SAS exome

AF:

0.0607

Gnomad4 FIN exome

AF:

0.0951

Gnomad4 NFE exome

AF:

0.0835

Gnomad4 OTH exome

AF:

0.0848

GnomAD4 genome

AF:

0.0969

AC:

14419

AN:

148794

Hom.:

716

Cov.:

AF XY:

0.0965

AC XY:

7006

AN XY:

72628

show subpopulations

Gnomad4 AFR

AF:

0.126

Gnomad4 AMR

AF:

0.0937

Gnomad4 ASJ

AF:

0.0816

Gnomad4 EAS

AF:

0.127

Gnomad4 SAS

AF:

0.0532

Gnomad4 FIN

AF:

0.0934

Gnomad4 NFE

AF:

0.0819

Gnomad4 OTH

AF:

0.105

Alfa

AF:

0.0852

Hom.:

319

Bravo

AF:

0.0982

Asia WGS

AF:

0.0840

AC:

292

AN:

3478

EpiCase

AF:

0.0796

EpiControl

AF:

0.0790

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 17, 2012	- -
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, criteria provided, single submitter	clinical testing	GeneDx	Jan 25, 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	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Feb 09, 2016	- -

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 06, 2017	- -

Myosclerosis

Benign:1

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

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Bethlem myopathy 1A

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.61

CADD

Benign

1.9

DANN

Benign

0.86

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