2-237371833-C-T

Position:

chr2-237371833-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BA1

The NM_004369.4(COL6A3):c.4184G>A(p.Arg1395Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00365 in 1,613,540 control chromosomes in the GnomAD database, including 170 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1395W) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0044 ( 13 hom., cov: 32)

Exomes 𝑓: 0.0036 ( 157 hom. )

Consequence

COL6A3
NM_004369.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:10

Conservation

PhyloP100: 0.596

Variant links:

Genes affected

COL6A3 (HGNC:2213): (collagen type VI alpha 3 chain) This gene encodes the alpha-3 chain, one of the three alpha chains of type VI collagen, a beaded filament collagen found in most connective tissues. The alpha-3 chain of type VI collagen is much larger than the alpha-1 and -2 chains. This difference in size is largely due to an increase in the number of subdomains, similar to von Willebrand Factor type A domains, that are found in the amino terminal globular domain of all the alpha chains. 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 the type VI collagen genes are associated with Bethlem myopathy, a rare autosomal dominant proximal myopathy with early childhood onset. Mutations in this gene are also a cause of Ullrich congenital muscular dystrophy, also referred to as Ullrich scleroatonic muscular dystrophy, an autosomal recessive congenital myopathy that is more severe than Bethlem myopathy. Multiple transcript variants have been identified, but the full-length nature of only some of these variants has been described. [provided by RefSeq, Jun 2009]

COL6A3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0020683706).

BP6

Variant 2-237371833-C-T is Benign according to our data. Variant chr2-237371833-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 94929.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=1, Benign=5}. Variant chr2-237371833-C-T is described in Lovd as [Pathogenic]. Variant chr2-237371833-C-T is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0716 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL6A3	NM_004369.4 linkuse as main transcript	c.4184G>A	p.Arg1395Gln	missense_variant	9/44	ENST00000295550.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL6A3	ENST00000295550.9 linkuse as main transcript	c.4184G>A	p.Arg1395Gln	missense_variant	9/44	1	NM_004369.4	P1	P12111-1

Frequencies

GnomAD3 genomes

AF:

0.00442

AC:

672

AN:

151966

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000628

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00813

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0783

Gnomad SAS

AF:

0.00418

Gnomad FIN

AF:

0.00519

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000588

Gnomad OTH

AF:

0.00192

GnomAD3 exomes

AF:

0.0100

AC:

2511

AN:

251046

Hom.:

AF XY:

0.00890

AC XY:

1208

AN XY:

135684

show subpopulations

Gnomad AFR exome

AF:

0.000615

Gnomad AMR exome

AF:

0.0242

Gnomad ASJ exome

AF:

0.000198

Gnomad EAS exome

AF:

0.0730

Gnomad SAS exome

AF:

0.00258

Gnomad FIN exome

AF:

0.00549

Gnomad NFE exome

AF:

0.000748

Gnomad OTH exome

AF:

0.00619

GnomAD4 exome

AF:

0.00358

AC:

5227

AN:

1461456

Hom.:

157

Cov.:

AF XY:

0.00347

AC XY:

2523

AN XY:

726996

show subpopulations

Gnomad4 AFR exome

AF:

0.000358

Gnomad4 AMR exome

AF:

0.0223

Gnomad4 ASJ exome

AF:

0.000153

Gnomad4 EAS exome

AF:

0.0757

Gnomad4 SAS exome

AF:

0.00241

Gnomad4 FIN exome

AF:

0.00713

Gnomad4 NFE exome

AF:

0.000325

Gnomad4 OTH exome

AF:

0.00414

GnomAD4 genome

AF:

0.00439

AC:

668

AN:

152084

Hom.:

Cov.:

AF XY:

0.00491

AC XY:

365

AN XY:

74312

show subpopulations

Gnomad4 AFR

AF:

0.000626

Gnomad4 AMR

AF:

0.00805

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.0779

Gnomad4 SAS

AF:

0.00418

Gnomad4 FIN

AF:

0.00519

Gnomad4 NFE

AF:

0.000588

Gnomad4 OTH

AF:

0.00190

Alfa

AF:

0.00411

Hom.:

Bravo

AF:

0.00548

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000581

AC:

ExAC

AF:

0.00920

AC:

1117

Asia WGS

AF:

0.0270

AC:

AN:

3478

EpiCase

AF:

0.000545

EpiControl

AF:

0.000296

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:10

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 23, 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, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 31, 2020	- -
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)	Dec 19, 2013	- -

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Nov 03, 2016	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Dystonia 27

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Department of Neurology, Xijing Hospital, Fourth Military Medical University

Oct 22, 2022

- -

Ullrich congenital muscular dystrophy 1A;C4225336:Dystonia 27;CN029274:Bethlem myopathy 1A

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 20, 2021

- -

Bethlem myopathy 1A

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Collagen 6-related myopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 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

0.084

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.30

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.15

.;T;.;T;.;.;.

Eigen

Benign

-0.33

Eigen_PC

Benign

-0.20

FATHMM_MKL

Benign

0.58

LIST_S2

Uncertain

0.89

D;D;D;D;.;D;D

MetaRNN

Benign

0.0021

T;T;T;T;T;T;T

MetaSVM

Benign

-0.86

MutationAssessor

Benign

0.46

.;N;.;.;.;.;.

MutationTaster

Benign

0.98

D;D;D;D;D;D;D;D

PrimateAI

Benign

0.27

PROVEAN

Benign

-0.57

N;N;N;.;N;N;N

REVEL

Benign

0.26

Sift

Benign

0.36

T;T;T;.;T;T;T

Sift4G

Benign

0.67

T;T;T;T;T;T;T

Polyphen

0.93

P;P;.;.;P;.;.

Vest4

0.21

MVP

0.84

MPC

0.49

ClinPred

0.017

GERP RS

4.8

Varity_R

0.080

gMVP

0.33

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