2-237336464-G-A

Position:

chr2-237336464-G-A

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2

The NM_004369.4(COL6A3):c.8636C>T(p.Thr2879Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00132 in 1,614,152 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00082 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0014 ( 4 hom. )

Consequence

COL6A3
NM_004369.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:4

Conservation

PhyloP100: 2.17

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 -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.083967686).

BP6

Variant 2-237336464-G-A is Benign according to our data. Variant chr2-237336464-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 284096.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Benign=1, Uncertain_significance=1}.

BS2

High Homozygotes in GnomAdExome4 at 4 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
COL6A3	NM_004369.4 linkuse as main transcript	c.8636C>T	p.Thr2879Met	missense_variant	40/44	ENST00000295550.9	NP_004360.2
COL6A3	NM_057167.4 linkuse as main transcript	c.8018C>T	p.Thr2673Met	missense_variant	39/43		NP_476508.2
COL6A3	NM_057166.5 linkuse as main transcript	c.6815C>T	p.Thr2272Met	missense_variant	37/41		NP_476507.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL6A3	ENST00000295550.9 linkuse as main transcript	c.8636C>T	p.Thr2879Met	missense_variant	40/44	1	NM_004369.4	ENSP00000295550	P1	P12111-1

Frequencies

GnomAD3 genomes

AF:

0.000821

AC:

125

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000458

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00123

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.000847

AC:

213

AN:

251490

Hom.:

AF XY:

0.000898

AC XY:

122

AN XY:

135918

show subpopulations

Gnomad AFR exome

AF:

0.000554

Gnomad AMR exome

AF:

0.000520

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.000980

Gnomad FIN exome

AF:

0.0000924

Gnomad NFE exome

AF:

0.00129

Gnomad OTH exome

AF:

0.000977

GnomAD4 exome

AF:

0.00137

AC:

2001

AN:

1461848

Hom.:

Cov.:

AF XY:

0.00129

AC XY:

936

AN XY:

727228

show subpopulations

Gnomad4 AFR exome

AF:

0.000209

Gnomad4 AMR exome

AF:

0.000581

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000985

Gnomad4 FIN exome

AF:

0.0000936

Gnomad4 NFE exome

AF:

0.00162

Gnomad4 OTH exome

AF:

0.00127

GnomAD4 genome

AF:

0.000821

AC:

125

AN:

152304

Hom.:

Cov.:

AF XY:

0.000725

AC XY:

AN XY:

74462

show subpopulations

Gnomad4 AFR

AF:

0.000457

Gnomad4 AMR

AF:

0.000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.00104

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00123

Gnomad4 OTH

AF:

0.00237

Alfa

AF:

0.00831

Hom.:

731

Bravo

AF:

0.000865

TwinsUK

AF:

0.00243

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.00136

AC:

ESP6500EA

AF:

0.00186

AC:

ExAC

AF:

0.000766

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00136

EpiControl

AF:

0.00101

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3Benign:2

Uncertain significance, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	COL6A3: BS1:Supporting -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 08, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 09, 2020	This variant is associated with the following publications: (PMID: 30564623) -

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

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 06, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.17

CADD

Benign

DANN

Benign

0.52

DEOGEN2

Benign

0.18

.;T;.;T;.

Eigen

Uncertain

0.22

Eigen_PC

Benign

0.044

FATHMM_MKL

Benign

0.58

LIST_S2

Benign

0.81

T;T;T;T;.

M_CAP

Pathogenic

0.56

MetaRNN

Benign

0.084

T;T;T;T;T

MetaSVM

Uncertain

0.11

MutationAssessor

Uncertain

2.4

.;M;.;.;.

MutationTaster

Benign

1.0

N;N;N;N;N;N

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.43

N;N;N;.;N

REVEL

Uncertain

0.36

Sift

Uncertain

0.0020

D;D;D;.;D

Sift4G

Pathogenic

0.0

D;D;D;D;D

Polyphen

1.0

D;D;.;.;D

Vest4

0.26

MVP

0.94

MPC

0.15

ClinPred

0.038

GERP RS

3.7

Varity_R

0.068

gMVP

0.22

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