rs117931394

Positions:

chr21-46132472-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.2980G>A(p.Ala994Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00551 in 1,606,384 control chromosomes in the GnomAD database, including 443 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A994A) has been classified as Benign.

Frequency

Genomes: 𝑓 0.0064 ( 55 hom., cov: 34)

Exomes 𝑓: 0.0054 ( 388 hom. )

Consequence

COL6A2
NM_001849.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 0.967

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=0.001766324).

BP6

Variant 21-46132472-G-A is Benign according to our data. Variant chr21-46132472-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 128815.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46132472-G-A is described in Lovd as [Benign]. Variant chr21-46132472-G-A is described in Lovd as [Pathogenic].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.12 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.2980G>A	p.Ala994Thr	missense_variant	28/28	ENST00000300527.9	NP_001840.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL6A2	ENST00000300527.9 linkuse as main transcript	c.2980G>A	p.Ala994Thr	missense_variant	28/28	1	NM_001849.4	ENSP00000300527	P1	P12110-1

Frequencies

GnomAD3 genomes

AF:

0.00646

AC:

984

AN:

152232

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000627

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000850

Gnomad ASJ

AF:

0.00346

Gnomad EAS

AF:

0.128

Gnomad SAS

AF:

0.00889

Gnomad FIN

AF:

0.0119

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00131

Gnomad OTH

AF:

0.00525

GnomAD3 exomes

AF:

0.0119

AC:

2860

AN:

240140

Hom.:

164

AF XY:

0.0108

AC XY:

1410

AN XY:

131152

show subpopulations

Gnomad AFR exome

AF:

0.000636

Gnomad AMR exome

AF:

0.000349

Gnomad ASJ exome

AF:

0.00254

Gnomad EAS exome

AF:

0.123

Gnomad SAS exome

AF:

0.00493

Gnomad FIN exome

AF:

0.0126

Gnomad NFE exome

AF:

0.00152

Gnomad OTH exome

AF:

0.00654

GnomAD4 exome

AF:

0.00541

AC:

7868

AN:

1454032

Hom.:

388

Cov.:

AF XY:

0.00542

AC XY:

3920

AN XY:

723006

show subpopulations

Gnomad4 AFR exome

AF:

0.000180

Gnomad4 AMR exome

AF:

0.000337

Gnomad4 ASJ exome

AF:

0.00307

Gnomad4 EAS exome

AF:

0.128

Gnomad4 SAS exome

AF:

0.00518

Gnomad4 FIN exome

AF:

0.0114

Gnomad4 NFE exome

AF:

0.00112

Gnomad4 OTH exome

AF:

0.00728

GnomAD4 genome

AF:

0.00645

AC:

982

AN:

152352

Hom.:

Cov.:

AF XY:

0.00796

AC XY:

593

AN XY:

74494

show subpopulations

Gnomad4 AFR

AF:

0.000625

Gnomad4 AMR

AF:

0.000849

Gnomad4 ASJ

AF:

0.00346

Gnomad4 EAS

AF:

0.128

Gnomad4 SAS

AF:

0.00890

Gnomad4 FIN

AF:

0.0119

Gnomad4 NFE

AF:

0.00131

Gnomad4 OTH

AF:

0.00425

Alfa

AF:

0.00694

Hom.:

Bravo

AF:

0.00704

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.000909

AC:

ESP6500EA

AF:

0.00116

AC:

ExAC

AF:

0.0116

AC:

1408

Asia WGS

AF:

0.0420

AC:

145

AN:

3478

EpiCase

AF:

0.00115

EpiControl

AF:

0.000830

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

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	GeneDx	Jun 10, 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, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 09, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 31, 2015	- -

Myosclerosis

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Glutamate formiminotransferase deficiency

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

Labcorp Genetics (formerly Invitae), Labcorp

Jan 26, 2024

- -

Collagen 6-related myopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not provided

Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Ullrich congenital muscular dystrophy 1A;C1850671:Myosclerosis;CN029274:Bethlem myopathy 1A

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Feb 25, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.38

CADD

Benign

DANN

Benign

0.91

DEOGEN2

Benign

0.17

Eigen

Benign

-0.41

Eigen_PC

Benign

-0.34

FATHMM_MKL

Benign

0.69

LIST_S2

Benign

0.77

MetaRNN

Benign

0.0018

MetaSVM

Benign

-1.2

MutationAssessor

Benign

0.77

MutationTaster

Benign

1.0

PrimateAI

Benign

0.35

PROVEAN

Benign

-0.35

REVEL

Benign

0.16

Sift

Benign

0.51

Sift4G

Benign

0.22

Polyphen

0.55

Vest4

0.062

MPC

0.14

ClinPred

0.0053

GERP RS

2.4

Varity_R

0.016

gMVP

0.62

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