21-46115902-G-A

Position:

chr21-46115902-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.832G>A(p.Glu278Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00173 in 1,612,902 control chromosomes in the GnomAD database, including 39 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0092 ( 21 hom., cov: 32)

Exomes 𝑓: 0.00095 ( 18 hom. )

Consequence

COL6A2
NM_001849.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 1.80

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=0.008608341).

BP6

Variant 21-46115902-G-A is Benign according to our data. Variant chr21-46115902-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 93961.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46115902-G-A is described in Lovd as [Benign]. Variant chr21-46115902-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00923 (1406/152272) while in subpopulation AFR AF= 0.0306 (1272/41558). AF 95% confidence interval is 0.0292. There are 21 homozygotes in gnomad4. There are 685 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 21 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
COL6A2	NM_001849.4 linkuse as main transcript	c.832G>A	p.Glu278Lys	missense_variant	6/28	ENST00000300527.9	NP_001840.3
COL6A2	NM_058174.3 linkuse as main transcript	c.832G>A	p.Glu278Lys	missense_variant	6/28	ENST00000397763.6	NP_478054.2
COL6A2	NM_058175.3 linkuse as main transcript	c.832G>A	p.Glu278Lys	missense_variant	6/28		NP_478055.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL6A2	ENST00000300527.9 linkuse as main transcript	c.832G>A	p.Glu278Lys	missense_variant	6/28	1	NM_001849.4	ENSP00000300527	P1	P12110-1
COL6A2	ENST00000397763.6 linkuse as main transcript	c.832G>A	p.Glu278Lys	missense_variant	6/28	5	NM_058174.3	ENSP00000380870		P12110-2
COL6A2	ENST00000409416.6 linkuse as main transcript	c.832G>A	p.Glu278Lys	missense_variant	5/27	5		ENSP00000387115		P12110-3
COL6A2	ENST00000485591.1 linkuse as main transcript	n.488G>A		non_coding_transcript_exon_variant	2/7	3

Frequencies

GnomAD3 genomes

AF:

0.00921

AC:

1401

AN:

152154

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0306

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00688

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000191

Gnomad OTH

AF:

0.00766

GnomAD3 exomes

AF:

0.00228

AC:

569

AN:

249318

Hom.:

AF XY:

0.00168

AC XY:

227

AN XY:

135280

show subpopulations

Gnomad AFR exome

AF:

0.0312

Gnomad AMR exome

AF:

0.00162

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000712

Gnomad OTH exome

AF:

0.000657

GnomAD4 exome

AF:

0.000948

AC:

1385

AN:

1460630

Hom.:

Cov.:

AF XY:

0.000824

AC XY:

599

AN XY:

726608

show subpopulations

Gnomad4 AFR exome

AF:

0.0330

Gnomad4 AMR exome

AF:

0.00179

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000405

Gnomad4 OTH exome

AF:

0.00232

GnomAD4 genome

AF:

0.00923

AC:

1406

AN:

152272

Hom.:

Cov.:

AF XY:

0.00920

AC XY:

685

AN XY:

74458

show subpopulations

Gnomad4 AFR

AF:

0.0306

Gnomad4 AMR

AF:

0.00687

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000191

Gnomad4 OTH

AF:

0.00758

Alfa

AF:

0.00230

Hom.:

Bravo

AF:

0.0106

ESP6500AA

AF:

0.0239

AC:

105

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.00252

AC:

306

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 18, 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. -
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. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 16, 2012	- -

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 03, 2017	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.14

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.34

T;.;.;.

Eigen

Benign

-0.21

Eigen_PC

Benign

-0.19

FATHMM_MKL

Benign

0.42

LIST_S2

Uncertain

0.94

D;T;.;D

MetaRNN

Benign

0.0086

T;T;T;T

MetaSVM

Uncertain

-0.22

MutationAssessor

Benign

1.2

L;L;L;L

MutationTaster

Benign

0.99

N;N;N;N;N

PrimateAI

Uncertain

0.62

PROVEAN

Benign

-0.99

N;N;N;N

REVEL

Uncertain

0.31

Sift

Benign

0.11

T;T;T;T

Sift4G

Benign

0.42

T;T;T;T

Polyphen

0.90

P;P;P;P

Vest4

0.54

MVP

0.97

MPC

0.55

ClinPred

0.016

GERP RS

4.0

Varity_R

0.27

gMVP

0.51

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