2-237359074-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBA1

The NM_004369.4(COL6A3):c.6369G>A(p.Leu2123Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.173 in 1,612,952 control chromosomes in the GnomAD database, including 30,488 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L2123L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.25 ( 6552 hom., cov: 33)

Exomes 𝑓: 0.16 ( 23936 hom. )

Consequence

COL6A3
NM_004369.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: -0.0350

Publications

20 publications found

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 Gene-Disease associations (from GenCC):

Bethlem myopathy 1A
Inheritance: AD, AR, SD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Ambry Genetics
collagen 6-related myopathy
Inheritance: AD, AR Classification: DEFINITIVE Submitted by: ClinGen
Ullrich congenital muscular dystrophy 1C
Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
dystonia 27
Inheritance: AR Classification: STRONG, SUPPORTIVE, LIMITED, NO_KNOWN Submitted by: Illumina, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics, Orphanet
Ullrich congenital muscular dystrophy 1A
Inheritance: AR, AD, SD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp
Bethlem myopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Ullrich congenital muscular dystrophy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

COL6A3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -18 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.31).

BP6

Variant 2-237359074-C-T is Benign according to our data. Variant chr2-237359074-C-T is described in ClinVar as [Benign]. Clinvar id is 94962.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.463 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL6A3	NM_004369.4 link	c.6369G>A	p.Leu2123Leu	synonymous_variant	Exon 20 of 44	ENST00000295550.9	NP_004360.2	P12111-1D9ZGF2Q8N4Z1Q63HQ4
COL6A3	NM_057167.4 link	c.5751G>A	p.Leu1917Leu	synonymous_variant	Exon 19 of 43		NP_476508.2	P12111-2Q8N4Z1Q63HQ4
COL6A3	NM_057166.5 link	c.4548G>A	p.Leu1516Leu	synonymous_variant	Exon 17 of 41		NP_476507.3	P12111-4B7ZW00

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
COL6A3	ENST00000295550.9 link	c.6369G>A	p.Leu2123Leu	synonymous_variant	Exon 20 of 44	1	NM_004369.4	ENSP00000295550.4	P12111-1
COL6A3	ENST00000472056.5 link	c.4548G>A	p.Leu1516Leu	synonymous_variant	Exon 17 of 41	1		ENSP00000418285.1	P12111-4
COL6A3	ENST00000353578.9 link	c.5751G>A	p.Leu1917Leu	synonymous_variant	Exon 19 of 43	5		ENSP00000315873.4	P12111-2

Frequencies

GnomAD3 genomes

AF:

0.253

AC:

38527

AN:

152028

Hom.:

6518

Cov.:

show subpopulations

Gnomad AFR

AF:

0.468

Gnomad AMI

AF:

0.139

Gnomad AMR

AF:

0.277

Gnomad ASJ

AF:

0.172

Gnomad EAS

AF:

0.355

Gnomad SAS

AF:

0.261

Gnomad FIN

AF:

0.121

Gnomad MID

AF:

0.253

Gnomad NFE

AF:

0.136

Gnomad OTH

AF:

0.244

GnomAD2 exomes

AF:

0.213

AC:

53684

AN:

251486

AF XY:

0.206

show subpopulations

Gnomad AFR exome

AF:

0.487

Gnomad AMR exome

AF:

0.289

Gnomad ASJ exome

AF:

0.170

Gnomad EAS exome

AF:

0.360

Gnomad FIN exome

AF:

0.127

Gnomad NFE exome

AF:

0.139

Gnomad OTH exome

AF:

0.179

GnomAD4 exome

AF:

0.165

AC:

240631

AN:

1460806

Hom.:

23936

Cov.:

AF XY:

0.166

AC XY:

120329

AN XY:

726750

show subpopulations

African (AFR)

AF:

0.489

AC:

16339

AN:

33428

American (AMR)

AF:

0.288

AC:

12882

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.163

AC:

4264

AN:

26132

East Asian (EAS)

AF:

0.335

AC:

13307

AN:

39688

South Asian (SAS)

AF:

0.251

AC:

21637

AN:

86218

European-Finnish (FIN)

AF:

0.124

AC:

6626

AN:

53420

Middle Eastern (MID)

AF:

0.225

AC:

1294

AN:

5762

European-Non Finnish (NFE)

AF:

0.138

AC:

152977

AN:

1111080

Other (OTH)

AF:

0.187

AC:

11305

AN:

60356

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

Heterozygous variant carriers

11538

23077

34615

46154

57692

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.254

AC:

38623

AN:

152146

Hom.:

6552

Cov.:

AF XY:

0.256

AC XY:

19024

AN XY:

74396

show subpopulations

African (AFR)

AF:

0.468

AC:

19423

AN:

41472

American (AMR)

AF:

0.278

AC:

4247

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.172

AC:

598

AN:

3472

East Asian (EAS)

AF:

0.355

AC:

1838

AN:

5174

South Asian (SAS)

AF:

0.262

AC:

1262

AN:

4812

European-Finnish (FIN)

AF:

0.121

AC:

1280

AN:

10610

Middle Eastern (MID)

AF:

0.252

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.136

AC:

9250

AN:

68006

Other (OTH)

AF:

0.248

AC:

524

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1335

2670

4006

5341

6676

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.182

Hom.:

10730

Bravo

AF:

0.273

Asia WGS

AF:

0.306

AC:

1067

AN:

3478

EpiCase

AF:

0.143

EpiControl

AF:

0.140

ClinVar

Significance: Benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:8

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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 49% 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: 46. Only high quality variants are reported. -

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jul 31, 2012

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 25, 2021

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

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 26, 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. -

Clinical Genetics, Academic Medical Center

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 13, 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

BayesDel_noAF

Benign

-0.31

CADD

Benign

8.5

(source)

DANN

Benign

0.74

PhyloP100

-0.035

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

2.0

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

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2-237359074-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over