chr2-237378645-C-A

Position:

chr2-237378645-C-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_004369.4(COL6A3):c.2488G>T(p.Ala830Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00885 in 1,612,522 control chromosomes in the GnomAD database, including 533 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 Benign (★★).

Frequency

Genomes: 𝑓 0.012 ( 66 hom., cov: 33)

Exomes 𝑓: 0.0085 ( 467 hom. )

Consequence

COL6A3
NM_004369.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 0.0430

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=0.001642257).

BP6

Variant 2-237378645-C-A is Benign according to our data. Variant chr2-237378645-C-A is described in ClinVar as [Benign]. Clinvar id is 94916.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-237378645-C-A is described in Lovd as [Benign]. Variant chr2-237378645-C-A is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0562 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL6A3	NM_004369.4 linkuse as main transcript	c.2488G>T	p.Ala830Ser	missense_variant	6/44	ENST00000295550.9	NP_004360.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL6A3	ENST00000295550.9 linkuse as main transcript	c.2488G>T	p.Ala830Ser	missense_variant	6/44	1	NM_004369.4	ENSP00000295550	P1	P12111-1

Frequencies

GnomAD3 genomes

AF:

0.0122

AC:

1850

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00237

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0592

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.0456

Gnomad SAS

AF:

0.0333

Gnomad FIN

AF:

0.0339

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000941

Gnomad OTH

AF:

0.0115

GnomAD3 exomes

AF:

0.0265

AC:

6653

AN:

251296

Hom.:

307

AF XY:

0.0237

AC XY:

3216

AN XY:

135864

show subpopulations

Gnomad AFR exome

AF:

0.00166

Gnomad AMR exome

AF:

0.112

Gnomad ASJ exome

AF:

0.000794

Gnomad EAS exome

AF:

0.0432

Gnomad SAS exome

AF:

0.0342

Gnomad FIN exome

AF:

0.0288

Gnomad NFE exome

AF:

0.00146

Gnomad OTH exome

AF:

0.0184

GnomAD4 exome

AF:

0.00850

AC:

12416

AN:

1460242

Hom.:

467

Cov.:

AF XY:

0.00873

AC XY:

6342

AN XY:

726428

show subpopulations

Gnomad4 AFR exome

AF:

0.00171

Gnomad4 AMR exome

AF:

0.106

Gnomad4 ASJ exome

AF:

0.00122

Gnomad4 EAS exome

AF:

0.0487

Gnomad4 SAS exome

AF:

0.0318

Gnomad4 FIN exome

AF:

0.0266

Gnomad4 NFE exome

AF:

0.000780

Gnomad4 OTH exome

AF:

0.0106

GnomAD4 genome

AF:

0.0121

AC:

1850

AN:

152280

Hom.:

Cov.:

AF XY:

0.0152

AC XY:

1131

AN XY:

74468

show subpopulations

Gnomad4 AFR

AF:

0.00236

Gnomad4 AMR

AF:

0.0594

Gnomad4 ASJ

AF:

0.000576

Gnomad4 EAS

AF:

0.0451

Gnomad4 SAS

AF:

0.0331

Gnomad4 FIN

AF:

0.0339

Gnomad4 NFE

AF:

0.000941

Gnomad4 OTH

AF:

0.0114

Alfa

AF:

0.00171

Hom.:

Bravo

AF:

0.0143

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00159

AC:

ESP6500EA

AF:

0.000930

AC:

ExAC

AF:

0.0226

AC:

2748

Asia WGS

AF:

0.0540

AC:

188

AN:

3478

EpiCase

AF:

0.000709

EpiControl

AF:

0.000356

ClinVar

Significance: 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	Mar 18, 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, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 14, 2014	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided

Benign:4

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 26, 2018	- -

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. -

Bethlem myopathy 1A

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.36

CADD

Benign

DANN

Benign

0.88

DEOGEN2

Benign

0.17

.;T;.;.;.

Eigen

Benign

-0.59

Eigen_PC

Benign

-0.57

FATHMM_MKL

Benign

0.51

LIST_S2

Benign

0.70

T;T;.;T;T

MetaRNN

Benign

0.0016

T;T;T;T;T

MetaSVM

Benign

-0.70

MutationAssessor

Benign

0.63

.;N;.;.;.

MutationTaster

Benign

1.0

D;D;N;N;N;N;N;N

PrimateAI

Benign

0.30

PROVEAN

Benign

-1.1

N;N;N;N;N

REVEL

Benign

0.081

Sift

Benign

0.28

T;T;T;T;T

Sift4G

Benign

0.073

T;T;T;T;T

Polyphen

0.86

P;B;P;.;.

Vest4

0.14

MPC

0.17

ClinPred

0.0030

GERP RS

0.19

Varity_R

0.054

gMVP

0.25

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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