rs1131296

Positions:

chr2-237334649-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.9206C>T(p.Thr3069Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.385 in 1,612,638 control chromosomes in the GnomAD database, including 121,469 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.37 ( 10885 hom., cov: 32)

Exomes 𝑓: 0.39 ( 110584 hom. )

Consequence

COL6A3
NM_004369.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.655

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=7.188022E-4).

BP6

Variant 2-237334649-G-A is Benign according to our data. Variant chr2-237334649-G-A is described in ClinVar as [Benign]. Clinvar id is 95018.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-237334649-G-A is described in Lovd as [Benign].

BA1

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
COL6A3	NM_004369.4 linkuse as main transcript	c.9206C>T	p.Thr3069Ile	missense_variant	41/44	ENST00000295550.9
COL6A3	NM_057167.4 linkuse as main transcript	c.8588C>T	p.Thr2863Ile	missense_variant	40/43
COL6A3	NM_057166.5 linkuse as main transcript	c.7385C>T	p.Thr2462Ile	missense_variant	38/41

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL6A3	ENST00000295550.9 linkuse as main transcript	c.9206C>T	p.Thr3069Ile	missense_variant	41/44	1	NM_004369.4	P1	P12111-1

Frequencies

GnomAD3 genomes

AF:

0.370

AC:

56226

AN:

151894

Hom.:

10891

Cov.:

show subpopulations

Gnomad AFR

AF:

0.282

Gnomad AMI

AF:

0.523

Gnomad AMR

AF:

0.351

Gnomad ASJ

AF:

0.397

Gnomad EAS

AF:

0.478

Gnomad SAS

AF:

0.328

Gnomad FIN

AF:

0.504

Gnomad MID

AF:

0.446

Gnomad NFE

AF:

0.397

Gnomad OTH

AF:

0.389

GnomAD3 exomes

AF:

0.385

AC:

96600

AN:

250848

Hom.:

19221

AF XY:

0.388

AC XY:

52635

AN XY:

135576

show subpopulations

Gnomad AFR exome

AF:

0.275

Gnomad AMR exome

AF:

0.311

Gnomad ASJ exome

AF:

0.390

Gnomad EAS exome

AF:

0.476

Gnomad SAS exome

AF:

0.328

Gnomad FIN exome

AF:

0.493

Gnomad NFE exome

AF:

0.402

Gnomad OTH exome

AF:

0.409

GnomAD4 exome

AF:

0.386

AC:

564375

AN:

1460626

Hom.:

110584

Cov.:

AF XY:

0.386

AC XY:

280206

AN XY:

726618

show subpopulations

Gnomad4 AFR exome

AF:

0.278

Gnomad4 AMR exome

AF:

0.316

Gnomad4 ASJ exome

AF:

0.396

Gnomad4 EAS exome

AF:

0.505

Gnomad4 SAS exome

AF:

0.328

Gnomad4 FIN exome

AF:

0.487

Gnomad4 NFE exome

AF:

0.388

Gnomad4 OTH exome

AF:

0.385

GnomAD4 genome

AF:

0.370

AC:

56228

AN:

152012

Hom.:

10885

Cov.:

AF XY:

0.375

AC XY:

27871

AN XY:

74290

show subpopulations

Gnomad4 AFR

AF:

0.282

Gnomad4 AMR

AF:

0.351

Gnomad4 ASJ

AF:

0.397

Gnomad4 EAS

AF:

0.479

Gnomad4 SAS

AF:

0.328

Gnomad4 FIN

AF:

0.504

Gnomad4 NFE

AF:

0.397

Gnomad4 OTH

AF:

0.388

Alfa

AF:

0.392

Hom.:

21607

Bravo

AF:

0.355

TwinsUK

AF:

0.391

AC:

1449

ALSPAC

AF:

0.385

AC:

1484

ESP6500AA

AF:

0.285

AC:

1256

ESP6500EA

AF:

0.402

AC:

3456

ExAC

AF:

0.388

AC:

47094

Asia WGS

AF:

0.385

AC:

1337

AN:

3478

EpiCase

AF:

0.398

EpiControl

AF:

0.402

ClinVar

Significance: Benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:9

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 09, 2012	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 14, 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. -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jul 31, 2024	This variant is classified as Benign based on local population frequency. This variant was detected in 45% 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: 42. Only high quality variants are reported. -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -

Bethlem myopathy 1A

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 30, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Dystonia 27

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

Collagen 6-related myopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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. -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Ullrich congenital muscular dystrophy 1A

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.76

BayesDel_noAF

Benign

-0.72

CADD

Benign

9.9

DANN

Benign

0.88

DEOGEN2

Benign

0.17

.;T;.;T;.

Eigen

Benign

-0.78

Eigen_PC

Benign

-0.70

FATHMM_MKL

Benign

0.48

LIST_S2

Benign

0.56

T;T;T;T;.

MetaRNN

Benign

0.00072

T;T;T;T;T

MetaSVM

Benign

-0.90

MutationAssessor

Benign

0.20

.;N;.;.;.

MutationTaster

Benign

0.99

P;P;P;P;P;P

PrimateAI

Benign

0.37

PROVEAN

Benign

-1.3

N;N;N;.;N

REVEL

Benign

0.034

Sift

Benign

0.26

T;T;T;.;T

Sift4G

Benign

0.24

T;T;T;T;T

Polyphen

0.0030

B;B;.;.;B

Vest4

0.052

MPC

0.16

ClinPred

0.0070

GERP RS

-1.1

Varity_R

0.042

gMVP

0.52

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