2-237353378-G-A

Position:

chr2-237353378-G-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.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. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as 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

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:

COL6A3 (HGNC:):

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=0.0039197206).

BP6

Variant 2-237353378-G-A is Benign according to our data. Variant chr2-237353378-G-A is described in ClinVar as [Benign]. Clinvar id is 94967.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-237353378-G-A is described in Lovd as [Benign]. Variant chr2-237353378-G-A is described in Lovd as [Likely_benign].

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/exons	MANE	Protein	UniProt
COL6A3	NM_004369.4 linkuse as main transcript	c.6653C>T	p.Pro2218Leu	missense_variant	25/44	ENST00000295550.9	NP_004360.2	P12111-1D9ZGF2Q8N4Z1Q63HQ4
COL6A3	NM_057167.4 linkuse as main transcript	c.6035C>T	p.Pro2012Leu	missense_variant	24/43		NP_476508.2	P12111-2Q8N4Z1Q63HQ4
COL6A3	NM_057166.5 linkuse as main transcript	c.4832C>T	p.Pro1611Leu	missense_variant	22/41		NP_476507.3	P12111-4B7ZW00

Ensembl

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

GnomAD3 exomes

AF:

0.0418

AC:

10515

AN:

251404

Hom.:

482

AF XY:

0.0396

AC XY:

5378

AN XY:

135872

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 SAS exome

AF:

0.0333

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

Gnomad4 AFR exome

AF:

0.182

Gnomad4 AMR exome

AF:

0.0310

Gnomad4 ASJ exome

AF:

0.0898

Gnomad4 EAS exome

AF:

0.00353

Gnomad4 SAS exome

AF:

0.0338

Gnomad4 FIN exome

AF:

0.0110

Gnomad4 NFE exome

AF:

0.0307

Gnomad4 OTH exome

AF:

0.0453

GnomAD4 genome

AF:

0.0719

AC:

10948

AN:

152194

Hom.:

713

Cov.:

AF XY:

0.0688

AC XY:

5123

AN XY:

74412

show subpopulations

Gnomad4 AFR

AF:

0.176

Gnomad4 AMR

AF:

0.0418

Gnomad4 ASJ

AF:

0.0936

Gnomad4 EAS

AF:

0.00501

Gnomad4 SAS

AF:

0.0314

Gnomad4 FIN

AF:

0.00904

Gnomad4 NFE

AF:

0.0328

Gnomad4 OTH

AF:

0.0736

Alfa

AF:

0.0432

Hom.:

449

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

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 17, 2012	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 31, 2022	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 17, 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. -

not provided

Benign:3

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Bethlem myopathy 1A

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Collagen 6-related myopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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. -

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

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;.;.;.

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

Splicing

Name

Calibrated prediction

Score

Prediction

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

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