rs36117715

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_004369.4(COL6A3):c.6653C>T(p.Pro2218Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0383 in 1,613,906 control chromosomes in the GnomAD database, including 2,181 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P2218P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.072 ( 713 hom., cov: 32)

Exomes 𝑓: 0.035 ( 1468 hom. )

Consequence

COL6A3
NM_004369.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.355

Publications

19 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0039197206).

BP6

Variant 2-237353378-G-A is Benign according to our data. Variant chr2-237353378-G-A is described in ClinVar as Benign. ClinVar VariationId is 94967.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.172 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL6A3	NM_004369.4 link	c.6653C>T	p.Pro2218Leu	missense_variant	Exon 25 of 44	ENST00000295550.9	NP_004360.2	P12111-1D9ZGF2Q8N4Z1Q63HQ4
COL6A3	NM_057167.4 link	c.6035C>T	p.Pro2012Leu	missense_variant	Exon 24 of 43		NP_476508.2	P12111-2Q8N4Z1Q63HQ4
COL6A3	NM_057166.5 link	c.4832C>T	p.Pro1611Leu	missense_variant	Exon 22 of 41		NP_476507.3	P12111-4B7ZW00

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
COL6A3	ENST00000295550.9 link	c.6653C>T	p.Pro2218Leu	missense_variant	Exon 25 of 44	1	NM_004369.4	ENSP00000295550.4	P12111-1
COL6A3	ENST00000472056.5 link	c.4832C>T	p.Pro1611Leu	missense_variant	Exon 22 of 41	1		ENSP00000418285.1	P12111-4
COL6A3	ENST00000353578.9 link	c.6035C>T	p.Pro2012Leu	missense_variant	Exon 24 of 43	5		ENSP00000315873.4	P12111-2
COL6A3	ENST00000491769.1 link	n.907C>T		non_coding_transcript_exon_variant	Exon 2 of 20	5

Frequencies

GnomAD3 genomes

AF:

0.0719

AC:

10936

AN:

152076

Hom.:

713

Cov.:

show subpopulations

Gnomad AFR

AF:

0.176

Gnomad AMI

AF:

0.0143

Gnomad AMR

AF:

0.0420

Gnomad ASJ

AF:

0.0936

Gnomad EAS

AF:

0.00519

Gnomad SAS

AF:

0.0315

Gnomad FIN

AF:

0.00904

Gnomad MID

AF:

0.0918

Gnomad NFE

AF:

0.0328

Gnomad OTH

AF:

0.0744

GnomAD2 exomes

AF:

0.0418

AC:

10515

AN:

251404

AF XY:

0.0396

show subpopulations

Gnomad AFR exome

AF:

0.186

Gnomad AMR exome

AF:

0.0297

Gnomad ASJ exome

AF:

0.0911

Gnomad EAS exome

AF:

0.00457

Gnomad FIN exome

AF:

0.00879

Gnomad NFE exome

AF:

0.0350

Gnomad OTH exome

AF:

0.0446

GnomAD4 exome

AF:

0.0348

AC:

50855

AN:

1461712

Hom.:

1468

Cov.:

AF XY:

0.0346

AC XY:

25136

AN XY:

727194

show subpopulations

African (AFR)

AF:

0.182

AC:

6078

AN:

33470

American (AMR)

AF:

0.0310

AC:

1388

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0898

AC:

2347

AN:

26132

East Asian (EAS)

AF:

0.00353

AC:

140

AN:

39700

South Asian (SAS)

AF:

0.0338

AC:

2915

AN:

86252

European-Finnish (FIN)

AF:

0.0110

AC:

588

AN:

53388

Middle Eastern (MID)

AF:

0.0860

AC:

496

AN:

5768

European-Non Finnish (NFE)

AF:

0.0307

AC:

34169

AN:

1111890

Other (OTH)

AF:

0.0453

AC:

2734

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

2471

4942

7414

9885

12356

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1350

2700

4050

5400

6750

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0719

AC:

10948

AN:

152194

Hom.:

713

Cov.:

AF XY:

0.0688

AC XY:

5123

AN XY:

74412

show subpopulations

African (AFR)

AF:

0.176

AC:

7286

AN:

41470

American (AMR)

AF:

0.0418

AC:

640

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.0936

AC:

325

AN:

3472

East Asian (EAS)

AF:

0.00501

AC:

AN:

5186

South Asian (SAS)

AF:

0.0314

AC:

151

AN:

4816

European-Finnish (FIN)

AF:

0.00904

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.0884

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0328

AC:

2230

AN:

68028

Other (OTH)

AF:

0.0736

AC:

155

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

486

972

1459

1945

2431

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

122

244

366

488

610

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0466

Hom.:

1031

Bravo

AF:

0.0801

TwinsUK

AF:

0.0297

AC:

110

ALSPAC

AF:

0.0304

AC:

117

ESP6500AA

AF:

0.173

AC:

761

ESP6500EA

AF:

0.0371

AC:

319

ExAC

AF:

0.0454

AC:

5508

Asia WGS

AF:

0.0230

AC:

AN:

3478

EpiCase

AF:

0.0371

EpiControl

AF:

0.0427

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 17, 2012

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 31, 2022

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

- -

Feb 17, 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. -

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:3

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Clinical Genetics, Academic Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

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. -

Bethlem myopathy 1A

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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

0.070

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.28

CADD

Benign

(source)

DANN

Benign

0.39

DEOGEN2

Benign

0.30

.;T;.;T;.

Eigen

Benign

-0.96

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.16

LIST_S2

Uncertain

0.86

D;D;D;D;.

MetaRNN

Benign

0.0039

T;T;T;T;T

MetaSVM

Benign

-0.76

MutationAssessor

Uncertain

2.3

.;M;.;.;.

PhyloP100

0.35

PrimateAI

Benign

0.30

PROVEAN

Uncertain

-3.5

D;D;D;.;D

REVEL

Benign

0.24

Sift

Benign

0.37

T;T;T;.;T

Sift4G

Uncertain

0.014

D;D;D;D;D

Polyphen

0.017

B;B;.;.;B

Vest4

0.13

MPC

0.15

ClinPred

0.010

GERP RS

-1.3

Varity_R

0.059

gMVP

0.21

Mutation Taster

=97/3

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

2.0

SpliceAI score (max)

0.090

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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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