rs142709940

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_ModerateBP6

The NM_001849.4(COL6A2):c.1769C>T(p.Thr590Met) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00246 in 1,612,876 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T590K) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0017 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0025 ( 9 hom. )

Consequence

COL6A2
NM_001849.4 missense, splice_region

Scores

Splicing: ADA: 0.6823

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:6

Conservation

PhyloP100: 6.25

Variant links:

Genes affected

COL6A2 (HGNC:2212): (collagen type VI alpha 2 chain) This gene encodes one of the three alpha chains of type VI collagen, a beaded filament collagen found in most connective tissues. The product of this gene contains several domains similar to von Willebrand Factor type A domains. 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 this gene are associated with Bethlem myopathy and Ullrich scleroatonic muscular dystrophy. Three transcript variants have been identified for this gene. [provided by RefSeq, Jul 2008]

COL6A2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.077075034).

BP6

Variant 21-46124919-C-T is Benign according to our data. Variant chr21-46124919-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 93920.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Uncertain_significance=1, Benign=1}. Variant chr21-46124919-C-T is described in Lovd as [Likely_pathogenic]. Variant chr21-46124919-C-T is described in Lovd as [Pathogenic]. Variant chr21-46124919-C-T is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
COL6A2	NM_001849.4 linkuse as main transcript	c.1769C>T	p.Thr590Met	missense_variant, splice_region_variant	23/28	ENST00000300527.9
COL6A2	NM_058174.3 linkuse as main transcript	c.1769C>T	p.Thr590Met	missense_variant, splice_region_variant	23/28	ENST00000397763.6
COL6A2	NM_058175.3 linkuse as main transcript	c.1769C>T	p.Thr590Met	missense_variant, splice_region_variant	23/28

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL6A2	ENST00000300527.9 linkuse as main transcript	c.1769C>T	p.Thr590Met	missense_variant, splice_region_variant	23/28	1	NM_001849.4	P1	P12110-1
COL6A2	ENST00000397763.6 linkuse as main transcript	c.1769C>T	p.Thr590Met	missense_variant, splice_region_variant	23/28	5	NM_058174.3		P12110-2
COL6A2	ENST00000409416.6 linkuse as main transcript	c.1769C>T	p.Thr590Met	missense_variant, splice_region_variant	22/27	5			P12110-3
COL6A2	ENST00000413758.1 linkuse as main transcript	c.392C>T	p.Thr131Met	missense_variant, splice_region_variant	8/11	3

Frequencies

GnomAD3 genomes

AF:

0.00168

AC:

256

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000603

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00111

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000830

Gnomad FIN

AF:

0.00122

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00288

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.00187

AC:

467

AN:

250244

Hom.:

AF XY:

0.00174

AC XY:

236

AN XY:

135696

show subpopulations

Gnomad AFR exome

AF:

0.000434

Gnomad AMR exome

AF:

0.00243

Gnomad ASJ exome

AF:

0.000299

Gnomad EAS exome

AF:

0.000163

Gnomad SAS exome

AF:

0.00105

Gnomad FIN exome

AF:

0.00143

Gnomad NFE exome

AF:

0.00262

Gnomad OTH exome

AF:

0.00197

GnomAD4 exome

AF:

0.00254

AC:

3708

AN:

1460548

Hom.:

Cov.:

AF XY:

0.00248

AC XY:

1804

AN XY:

726582

show subpopulations

Gnomad4 AFR exome

AF:

0.000538

Gnomad4 AMR exome

AF:

0.00219

Gnomad4 ASJ exome

AF:

0.000344

Gnomad4 EAS exome

AF:

0.000126

Gnomad4 SAS exome

AF:

0.000916

Gnomad4 FIN exome

AF:

0.00178

Gnomad4 NFE exome

AF:

0.00295

Gnomad4 OTH exome

AF:

0.00199

GnomAD4 genome

AF:

0.00168

AC:

256

AN:

152328

Hom.:

Cov.:

AF XY:

0.00175

AC XY:

130

AN XY:

74486

show subpopulations

Gnomad4 AFR

AF:

0.000601

Gnomad4 AMR

AF:

0.00111

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000830

Gnomad4 FIN

AF:

0.00122

Gnomad4 NFE

AF:

0.00288

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.00171

Hom.:

Bravo

AF:

0.00160

TwinsUK

AF:

0.00216

AC:

ALSPAC

AF:

0.00259

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00244

AC:

ExAC

AF:

0.00165

AC:

200

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00251

EpiControl

AF:

0.00267

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 26, 2021	This variant is associated with the following publications: (PMID: 25380242, 18378883, 25535305, 24038877, 31862442, 32528171) -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Apr 17, 2015

- -

Myosclerosis

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Bethlem myopathy 1A

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

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. -

COL6A2-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 05, 2021

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.30

BayesDel_addAF

Benign

-0.016

BayesDel_noAF

Pathogenic

0.21

Cadd

Pathogenic

Dann

Uncertain

1.0

DEOGEN2

Uncertain

0.56

D;.;.;.;T

Eigen

Uncertain

0.51

Eigen_PC

Uncertain

0.43

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

D;D;.;D;D

M_CAP

Pathogenic

0.84

MetaRNN

Benign

0.077

T;T;T;T;T

MetaSVM

Pathogenic

0.90

MutationAssessor

Uncertain

2.2

M;M;M;M;.

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Uncertain

0.78

PROVEAN

Uncertain

-3.1

D;D;D;D;D

REVEL

Pathogenic

0.71

Sift

Benign

0.034

D;D;D;D;D

Sift4G

Uncertain

0.029

D;D;D;D;D

Polyphen

1.0

D;D;D;D;.

Vest4

0.74

MVP

0.98

MPC

0.62

ClinPred

0.039

GERP RS

4.1

Varity_R

0.21

gMVP

0.56

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.68

dbscSNV1_RF

Benign

0.64

SpliceAI score (max)

0.14

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