rs12622093

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_004369.4(COL6A3):c.3129C>T(p.Gly1043Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.237 in 1,613,658 control chromosomes in the GnomAD database, including 46,183 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.21 ( 3454 hom., cov: 32)

Exomes 𝑓: 0.24 ( 42729 hom. )

Consequence

COL6A3
NM_004369.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: 0.246

Publications

16 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.5).

BP6

Variant 2-237374962-G-A is Benign according to our data. Variant chr2-237374962-G-A is described in ClinVar as [Benign]. Clinvar id is 94921.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.246 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.268 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL6A3	NM_004369.4 link	c.3129C>T	p.Gly1043Gly	synonymous_variant	Exon 8 of 44	ENST00000295550.9	NP_004360.2	P12111-1D9ZGF2Q8N4Z1Q63HQ4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL6A3	ENST00000295550.9 link	c.3129C>T	p.Gly1043Gly	synonymous_variant	Exon 8 of 44	1	NM_004369.4	ENSP00000295550.4		P12111-1

Frequencies

GnomAD3 genomes

AF:

0.209

AC:

31696

AN:

151802

Hom.:

3451

Cov.:

show subpopulations

Gnomad AFR

AF:

0.121

Gnomad AMI

AF:

0.156

Gnomad AMR

AF:

0.243

Gnomad ASJ

AF:

0.218

Gnomad EAS

AF:

0.280

Gnomad SAS

AF:

0.249

Gnomad FIN

AF:

0.253

Gnomad MID

AF:

0.294

Gnomad NFE

AF:

0.239

Gnomad OTH

AF:

0.222

GnomAD2 exomes

AF:

0.234

AC:

58220

AN:

248796

AF XY:

0.236

show subpopulations

Gnomad AFR exome

AF:

0.120

Gnomad AMR exome

AF:

0.236

Gnomad ASJ exome

AF:

0.197

Gnomad EAS exome

AF:

0.287

Gnomad FIN exome

AF:

0.255

Gnomad NFE exome

AF:

0.240

Gnomad OTH exome

AF:

0.229

GnomAD4 exome

AF:

0.240

AC:

350363

AN:

1461738

Hom.:

42729

Cov.:

AF XY:

0.240

AC XY:

174243

AN XY:

727164

show subpopulations

African (AFR)

AF:

0.116

AC:

3869

AN:

33480

American (AMR)

AF:

0.236

AC:

10553

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.198

AC:

5166

AN:

26136

East Asian (EAS)

AF:

0.263

AC:

10422

AN:

39698

South Asian (SAS)

AF:

0.233

AC:

20126

AN:

86258

European-Finnish (FIN)

AF:

0.251

AC:

13375

AN:

53292

Middle Eastern (MID)

AF:

0.238

AC:

1370

AN:

5768

European-Non Finnish (NFE)

AF:

0.244

AC:

271602

AN:

1111992

Other (OTH)

AF:

0.230

AC:

13880

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

16365

32731

49096

65462

81827

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.209

AC:

31716

AN:

151920

Hom.:

3454

Cov.:

AF XY:

0.214

AC XY:

15871

AN XY:

74226

show subpopulations

African (AFR)

AF:

0.120

AC:

4995

AN:

41472

American (AMR)

AF:

0.243

AC:

3704

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.218

AC:

755

AN:

3464

East Asian (EAS)

AF:

0.281

AC:

1437

AN:

5122

South Asian (SAS)

AF:

0.250

AC:

1199

AN:

4796

European-Finnish (FIN)

AF:

0.253

AC:

2662

AN:

10524

Middle Eastern (MID)

AF:

0.289

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.239

AC:

16262

AN:

67968

Other (OTH)

AF:

0.226

AC:

475

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1253

2505

3758

5010

6263

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.230

Hom.:

9393

Bravo

AF:

0.204

Asia WGS

AF:

0.257

AC:

896

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

Jul 31, 2012

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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 44% 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: 41. Only high quality variants are reported. -

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. -

Aug 15, 2013

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

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

-0.50

CADD

Benign

7.6

(source)

DANN

Benign

0.55

PhyloP100

0.25

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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rs12622093

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