2-237336320-A-G

Variant names:

Variant summary

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

The NM_004369.4(COL6A3):c.8780T>C(p.Met2927Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.64 in 1,613,978 control chromosomes in the GnomAD database, including 333,844 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 0.68 ( 35488 hom., cov: 33)

Exomes 𝑓: 0.64 ( 298356 hom. )

Consequence

COL6A3
NM_004369.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:15

Conservation

PhyloP100: 1.38

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=1.2549137E-6).

BP6

Variant 2-237336320-A-G is Benign according to our data. Variant chr2-237336320-A-G is described in ClinVar as [Benign]. Clinvar id is 95008.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-237336320-A-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.771 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL6A3	NM_004369.4 link	c.8780T>C	p.Met2927Thr	missense_variant	Exon 40 of 44	ENST00000295550.9	NP_004360.2	P12111-1D9ZGF2Q8N4Z1Q63HQ4
COL6A3	NM_057167.4 link	c.8162T>C	p.Met2721Thr	missense_variant	Exon 39 of 43		NP_476508.2	P12111-2Q8N4Z1Q63HQ4
COL6A3	NM_057166.5 link	c.6959T>C	p.Met2320Thr	missense_variant	Exon 37 of 41		NP_476507.3	P12111-4B7ZW00

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL6A3	ENST00000295550.9 link	c.8780T>C	p.Met2927Thr	missense_variant	Exon 40 of 44	1	NM_004369.4	ENSP00000295550.4		P12111-1

Frequencies

GnomAD3 genomes

AF:

0.678

AC:

103129

AN:

152028

Hom.:

35463

Cov.:

show subpopulations

Gnomad AFR

AF:

0.778

Gnomad AMI

AF:

0.776

Gnomad AMR

AF:

0.591

Gnomad ASJ

AF:

0.738

Gnomad EAS

AF:

0.536

Gnomad SAS

AF:

0.549

Gnomad FIN

AF:

0.720

Gnomad MID

AF:

0.778

Gnomad NFE

AF:

0.645

Gnomad OTH

AF:

0.694

GnomAD3 exomes

AF:

0.631

AC:

158412

AN:

251020

Hom.:

50943

AF XY:

0.632

AC XY:

85764

AN XY:

135788

show subpopulations

Gnomad AFR exome

AF:

0.782

Gnomad AMR exome

AF:

0.524

Gnomad ASJ exome

AF:

0.724

Gnomad EAS exome

AF:

0.532

Gnomad SAS exome

AF:

0.554

Gnomad FIN exome

AF:

0.714

Gnomad NFE exome

AF:

0.653

Gnomad OTH exome

AF:

0.660

GnomAD4 exome

AF:

0.636

AC:

930432

AN:

1461832

Hom.:

298356

Cov.:

AF XY:

0.634

AC XY:

461244

AN XY:

727218

show subpopulations

Gnomad4 AFR exome

AF:

0.788

Gnomad4 AMR exome

AF:

0.534

Gnomad4 ASJ exome

AF:

0.731

Gnomad4 EAS exome

AF:

0.567

Gnomad4 SAS exome

AF:

0.554

Gnomad4 FIN exome

AF:

0.705

Gnomad4 NFE exome

AF:

0.638

Gnomad4 OTH exome

AF:

0.645

GnomAD4 genome

AF:

0.678

AC:

103196

AN:

152146

Hom.:

35488

Cov.:

AF XY:

0.678

AC XY:

50390

AN XY:

74374

show subpopulations

Gnomad4 AFR

AF:

0.778

Gnomad4 AMR

AF:

0.591

Gnomad4 ASJ

AF:

0.738

Gnomad4 EAS

AF:

0.536

Gnomad4 SAS

AF:

0.548

Gnomad4 FIN

AF:

0.720

Gnomad4 NFE

AF:

0.645

Gnomad4 OTH

AF:

0.689

Alfa

AF:

0.654

Hom.:

81626

Bravo

AF:

0.675

TwinsUK

AF:

0.652

AC:

2419

ALSPAC

AF:

0.641

AC:

2469

ESP6500AA

AF:

0.780

AC:

3437

ESP6500EA

AF:

0.654

AC:

5621

ExAC

AF:

0.638

AC:

77488

Asia WGS

AF:

0.557

AC:

1940

AN:

3478

EpiCase

AF:

0.657

EpiControl

AF:

0.661

ClinVar

Significance: Benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:9

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 15, 2013

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 05, 2016

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 04, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jul 31, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 80% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy, Progressive Myoclonus Epilepsy and Abnormal Movements and Neurodegeneration with brain iron accumulation. Number of patients: 74. Only high quality variants are reported. -

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Bethlem myopathy 1A

Benign:2

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dystonia 27

Benign:1

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Collagen 6-related myopathy

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Ullrich congenital muscular dystrophy 1A

Benign:1

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.063

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.53

CADD

Benign

1.7

DANN

Benign

0.28

DEOGEN2

Benign

0.13

.;T;.;T;.

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.0012

LIST_S2

Benign

0.034

T;T;T;T;.

MetaRNN

Benign

0.0000013

T;T;T;T;T

MetaSVM

Benign

-0.94

MutationAssessor

Benign

-1.9

.;N;.;.;.

PrimateAI

Benign

0.28

PROVEAN

Benign

0.0

N;N;N;.;N

REVEL

Benign

0.16

Sift

Benign

1.0

T;T;T;.;T

Sift4G

Benign

0.66

T;T;T;T;T

Polyphen

0.0

B;B;.;.;B

Vest4

0.0090

MPC

0.17

ClinPred

0.00058

GERP RS

2.2

Varity_R

0.037

gMVP

0.058

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