2-237368568-C-T

Position:

chr2-237368568-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The ENST00000295550.9(COL6A3):c.4895G>A(p.Arg1632Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00506 in 1,614,030 control chromosomes in the GnomAD database, including 144 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1632W) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0057 ( 16 hom., cov: 32)

Exomes 𝑓: 0.0050 ( 128 hom. )

Consequence

COL6A3
ENST00000295550.9 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -0.909

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.003070861).

BP6

Variant 2-237368568-C-T is Benign according to our data. Variant chr2-237368568-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 94941.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-237368568-C-T is described in Lovd as [Benign]. Variant chr2-237368568-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00569 (866/152174) while in subpopulation EAS AF= 0.0385 (199/5174). AF 95% confidence interval is 0.0341. There are 16 homozygotes in gnomad4. There are 576 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 16 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
COL6A3	NM_004369.4 linkuse as main transcript	c.4895G>A	p.Arg1632Gln	missense_variant	10/44	ENST00000295550.9	NP_004360.2
COL6A3	NM_057167.4 linkuse as main transcript	c.4277G>A	p.Arg1426Gln	missense_variant	9/43		NP_476508.2
COL6A3	NM_057166.5 linkuse as main transcript	c.3074G>A	p.Arg1025Gln	missense_variant	7/41		NP_476507.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL6A3	ENST00000295550.9 linkuse as main transcript	c.4895G>A	p.Arg1632Gln	missense_variant	10/44	1	NM_004369.4	ENSP00000295550	P1	P12111-1
COL6A3	ENST00000472056.5 linkuse as main transcript	c.3074G>A	p.Arg1025Gln	missense_variant	7/41	1		ENSP00000418285		P12111-4
COL6A3	ENST00000353578.9 linkuse as main transcript	c.4277G>A	p.Arg1426Gln	missense_variant	9/43	5		ENSP00000315873		P12111-2
COL6A3	ENST00000684597.1 linkuse as main transcript	c.227G>A	p.Arg76Gln	missense_variant	2/3			ENSP00000508021

Frequencies

GnomAD3 genomes

AF:

0.00571

AC:

868

AN:

152058

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000266

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00111

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.0386

Gnomad SAS

AF:

0.0309

Gnomad FIN

AF:

0.0340

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.00156

Gnomad OTH

AF:

0.00622

GnomAD3 exomes

AF:

0.0101

AC:

2537

AN:

251206

Hom.:

AF XY:

0.0113

AC XY:

1538

AN XY:

135830

show subpopulations

Gnomad AFR exome

AF:

0.000369

Gnomad AMR exome

AF:

0.000838

Gnomad ASJ exome

AF:

0.00109

Gnomad EAS exome

AF:

0.0360

Gnomad SAS exome

AF:

0.0307

Gnomad FIN exome

AF:

0.0286

Gnomad NFE exome

AF:

0.00196

Gnomad OTH exome

AF:

0.00750

GnomAD4 exome

AF:

0.00499

AC:

7296

AN:

1461856

Hom.:

128

Cov.:

AF XY:

0.00572

AC XY:

4163

AN XY:

727226

show subpopulations

Gnomad4 AFR exome

AF:

0.000538

Gnomad4 AMR exome

AF:

0.000783

Gnomad4 ASJ exome

AF:

0.00103

Gnomad4 EAS exome

AF:

0.0371

Gnomad4 SAS exome

AF:

0.0284

Gnomad4 FIN exome

AF:

0.0266

Gnomad4 NFE exome

AF:

0.00119

Gnomad4 OTH exome

AF:

0.00813

GnomAD4 genome

AF:

0.00569

AC:

866

AN:

152174

Hom.:

Cov.:

AF XY:

0.00774

AC XY:

576

AN XY:

74378

show subpopulations

Gnomad4 AFR

AF:

0.000265

Gnomad4 AMR

AF:

0.00111

Gnomad4 ASJ

AF:

0.00144

Gnomad4 EAS

AF:

0.0385

Gnomad4 SAS

AF:

0.0310

Gnomad4 FIN

AF:

0.0340

Gnomad4 NFE

AF:

0.00156

Gnomad4 OTH

AF:

0.00616

Alfa

AF:

0.00282

Hom.:

Bravo

AF:

0.00272

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00116

AC:

ExAC

AF:

0.0105

AC:

1280

Asia WGS

AF:

0.0500

AC:

174

AN:

3478

EpiCase

AF:

0.00196

EpiControl

AF:

0.00124

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 08, 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	Eurofins Ntd Llc (ga)	Nov 05, 2012	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided

Benign:2

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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

Sep 21, 2021

- -

Bethlem myopathy 1A

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 30, 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

0.070

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.51

CADD

Benign

7.4

DANN

Benign

0.68

DEOGEN2

Benign

0.12

.;T;.;T;.

Eigen

Benign

-0.97

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.044

LIST_S2

Benign

0.82

T;T;T;T;.

MetaRNN

Benign

0.0031

T;T;T;T;T

MetaSVM

Benign

-0.90

MutationAssessor

Benign

1.6

.;L;.;.;.

MutationTaster

Benign

1.0

N;N;N;N;N;N

PrimateAI

Benign

0.32

PROVEAN

Benign

-0.42

N;N;N;.;N

REVEL

Benign

0.14

Sift

Benign

0.30

T;T;T;.;T

Sift4G

Benign

0.14

T;T;T;T;T

Polyphen

0.74

P;B;.;.;P

Vest4

0.11

MPC

0.18

ClinPred

0.012

GERP RS

-0.80

Varity_R

0.045

gMVP

0.27

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