rs138285547

Positions:

chr2-237341067-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6

The NM_004369.4(COL6A3):c.7849G>A(p.Asp2617Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000136 in 1,614,166 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts 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. D2617E) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00066 ( 1 hom., cov: 31)

Exomes 𝑓: 0.000081 ( 0 hom. )

Consequence

COL6A3
NM_004369.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:4

Conservation

PhyloP100: 4.90

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 Likely_benign. Variant got -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.017731786).

BP6

Variant 2-237341067-C-T is Benign according to our data. Variant chr2-237341067-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 285313.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Benign=1, Likely_benign=3}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
COL6A3	NM_004369.4 linkuse as main transcript	c.7849G>A	p.Asp2617Asn	missense_variant	38/44	ENST00000295550.9
COL6A3	NM_057167.4 linkuse as main transcript	c.7231G>A	p.Asp2411Asn	missense_variant	37/43
COL6A3	NM_057166.5 linkuse as main transcript	c.6028G>A	p.Asp2010Asn	missense_variant	35/41

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL6A3	ENST00000295550.9 linkuse as main transcript	c.7849G>A	p.Asp2617Asn	missense_variant	38/44	1	NM_004369.4	P1	P12111-1

Frequencies

GnomAD3 genomes

AF:

0.000664

AC:

101

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00227

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

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:

0.00

Gnomad OTH

AF:

0.000956

GnomAD3 exomes

AF:

0.000200

AC:

AN:

250624

Hom.:

AF XY:

0.000111

AC XY:

AN XY:

135454

show subpopulations

Gnomad AFR exome

AF:

0.00284

Gnomad AMR exome

AF:

0.000116

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000807

AC:

118

AN:

1461856

Hom.:

Cov.:

AF XY:

0.0000591

AC XY:

AN XY:

727226

show subpopulations

Gnomad4 AFR exome

AF:

0.00296

Gnomad4 AMR exome

AF:

0.0000894

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.000215

GnomAD4 genome

AF:

0.000663

AC:

101

AN:

152310

Hom.:

Cov.:

AF XY:

0.000645

AC XY:

AN XY:

74474

show subpopulations

Gnomad4 AFR

AF:

0.00226

Gnomad4 AMR

AF:

0.000327

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000946

Alfa

AF:

0.000131

Hom.:

Bravo

AF:

0.000963

ESP6500AA

AF:

0.00272

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000264

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 30, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 26, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 20, 2020	- -

Bethlem myopathy 1A

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 19, 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. -

COL6A3-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 22, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.44

CADD

Pathogenic

DANN

Uncertain

0.99

Eigen

Uncertain

0.50

Eigen_PC

Uncertain

0.52

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.96

D;D;D;D;.

M_CAP

Benign

0.013

MetaRNN

Benign

0.018

T;T;T;T;T

MetaSVM

Benign

-1.1

MutationTaster

Benign

1.0

D;D;D;D;D;D

PrimateAI

Uncertain

0.64

PROVEAN

Uncertain

-3.4

D;D;D;.;D

REVEL

Benign

0.20

Sift

Pathogenic

0.0

D;D;D;.;D

Sift4G

Pathogenic

0.0

D;D;D;D;D

Polyphen

0.99

D;D;.;.;D

Vest4

0.68

MVP

0.66

MPC

0.14

ClinPred

0.094

GERP RS

5.0

Varity_R

0.71

gMVP

0.62

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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