rs144484744

Positions:

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM1BP4_StrongBP6_Very_StrongBS2

The NM_001849.4(COL6A2):c.2599C>T(p.Arg867Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000647 in 1,597,858 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R867Q) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0012 ( 1 hom., cov: 34)

Exomes 𝑓: 0.00059 ( 4 hom. )

Consequence

COL6A2
NM_001849.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 1.72

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 6 benign, 8 uncertain in NM_001849.4

BP4

Computational evidence support a benign effect (MetaRNN=0.030291677).

BP6

Variant 21-46132091-C-T is Benign according to our data. Variant chr21-46132091-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 281164.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46132091-C-T is described in Lovd as [Likely_pathogenic]. Variant chr21-46132091-C-T is described in Lovd as [Pathogenic].

BS2

High Homozygotes in GnomAdExome4 at 4 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL6A2	NM_001849.4 linkuse as main transcript	c.2599C>T	p.Arg867Trp	missense_variant	28/28	ENST00000300527.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL6A2	ENST00000300527.9 linkuse as main transcript	c.2599C>T	p.Arg867Trp	missense_variant	28/28	1	NM_001849.4	P1	P12110-1

Frequencies

GnomAD3 genomes

AF:

0.00119

AC:

181

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000410

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00791

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00373

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000191

Gnomad OTH

AF:

0.00574

GnomAD3 exomes

AF:

0.00142

AC:

307

AN:

216436

Hom.:

AF XY:

0.00152

AC XY:

181

AN XY:

119158

show subpopulations

Gnomad AFR exome

AF:

0.000457

Gnomad AMR exome

AF:

0.00483

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000631

Gnomad SAS exome

AF:

0.00362

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000290

Gnomad OTH exome

AF:

0.00237

GnomAD4 exome

AF:

0.000590

AC:

853

AN:

1445552

Hom.:

Cov.:

AF XY:

0.000666

AC XY:

479

AN XY:

718850

show subpopulations

Gnomad4 AFR exome

AF:

0.000211

Gnomad4 AMR exome

AF:

0.00541

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000516

Gnomad4 SAS exome

AF:

0.00351

Gnomad4 FIN exome

AF:

0.0000211

Gnomad4 NFE exome

AF:

0.000227

Gnomad4 OTH exome

AF:

0.000987

GnomAD4 genome

AF:

0.00119

AC:

181

AN:

152306

Hom.:

Cov.:

AF XY:

0.00145

AC XY:

108

AN XY:

74480

show subpopulations

Gnomad4 AFR

AF:

0.000409

Gnomad4 AMR

AF:

0.00790

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00373

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000191

Gnomad4 OTH

AF:

0.00568

Alfa

AF:

0.000674

Hom.:

Bravo

AF:

0.00172

ESP6500AA

AF:

0.000228

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000963

AC:

115

Asia WGS

AF:

0.00202

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 11, 2020	This variant is associated with the following publications: (PMID: 24038877, 32528171) -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 26, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2022	COL6A2: BS2 -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Aug 17, 2015

- -

Bethlem myopathy 1A

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 30, 2023

- -

COL6A2-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 01, 2020

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

0.25

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Uncertain

-0.080

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.67

Eigen

Benign

-0.037

Eigen_PC

Benign

-0.26

FATHMM_MKL

Benign

0.17

LIST_S2

Uncertain

0.94

M_CAP

Pathogenic

0.54

MetaRNN

Benign

0.030

MetaSVM

Uncertain

0.082

MutationAssessor

Uncertain

2.1

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.59

PROVEAN

Uncertain

-3.5

REVEL

Uncertain

0.41

Sift

Uncertain

0.015

Sift4G

Uncertain

0.014

Polyphen

1.0

Vest4

0.64

MVP

0.99

MPC

0.62

ClinPred

0.022

GERP RS

3.2

Varity_R

0.18

gMVP

0.66

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