21-46117890-C-G

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM1BP4_StrongBP6

The NM_001849.4(COL6A2):c.1070C>G(p.Pro357Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00104 in 1,612,406 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. 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. P357L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0011 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0010 ( 3 hom. )

Consequence

COL6A2
NM_001849.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:5

Conservation

PhyloP100: 1.71

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.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 7 uncertain in NM_001849.4

BP4

Computational evidence support a benign effect (MetaRNN=0.037938148).

BP6

Variant 21-46117890-C-G is Benign according to our data. Variant chr21-46117890-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 194041.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=2, Benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
COL6A2	NM_001849.4 linkuse as main transcript	c.1070C>G	p.Pro357Arg	missense_variant	12/28	ENST00000300527.9
COL6A2	NM_058174.3 linkuse as main transcript	c.1070C>G	p.Pro357Arg	missense_variant	12/28	ENST00000397763.6
COL6A2	NM_058175.3 linkuse as main transcript	c.1070C>G	p.Pro357Arg	missense_variant	12/28

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL6A2	ENST00000300527.9 linkuse as main transcript	c.1070C>G	p.Pro357Arg	missense_variant	12/28	1	NM_001849.4	P1	P12110-1
COL6A2	ENST00000397763.6 linkuse as main transcript	c.1070C>G	p.Pro357Arg	missense_variant	12/28	5	NM_058174.3		P12110-2
COL6A2	ENST00000409416.6 linkuse as main transcript	c.1070C>G	p.Pro357Arg	missense_variant	11/27	5			P12110-3

Frequencies

GnomAD3 genomes

AF:

0.00106

AC:

161

AN:

152126

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000266

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00183

Gnomad ASJ

AF:

0.00691

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00135

Gnomad OTH

AF:

0.00192

GnomAD3 exomes

AF:

0.000975

AC:

241

AN:

247068

Hom.:

AF XY:

0.000985

AC XY:

132

AN XY:

134048

show subpopulations

Gnomad AFR exome

AF:

0.0000634

Gnomad AMR exome

AF:

0.00134

Gnomad ASJ exome

AF:

0.00564

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00118

Gnomad OTH exome

AF:

0.000997

GnomAD4 exome

AF:

0.00104

AC:

1520

AN:

1460162

Hom.:

Cov.:

AF XY:

0.00104

AC XY:

754

AN XY:

726280

show subpopulations

Gnomad4 AFR exome

AF:

0.000120

Gnomad4 AMR exome

AF:

0.00119

Gnomad4 ASJ exome

AF:

0.00690

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000465

Gnomad4 FIN exome

AF:

0.0000191

Gnomad4 NFE exome

AF:

0.00106

Gnomad4 OTH exome

AF:

0.00146

GnomAD4 genome

AF:

0.00106

AC:

161

AN:

152244

Hom.:

Cov.:

AF XY:

0.00116

AC XY:

AN XY:

74440

show subpopulations

Gnomad4 AFR

AF:

0.000265

Gnomad4 AMR

AF:

0.00183

Gnomad4 ASJ

AF:

0.00691

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00135

Gnomad4 OTH

AF:

0.00190

Alfa

AF:

0.00133

Hom.:

Bravo

AF:

0.000941

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.000456

AC:

ESP6500EA

AF:

0.00163

AC:

ExAC

AF:

0.000952

AC:

115

EpiCase

AF:

0.00109

EpiControl

AF:

0.00137

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 11, 2017	The P357R variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The P357R variant is observed in 96/58912 (0.16%) alleles from individuals of European background (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Additionally, in silico analysis predicts this variant is probably damaging to the protein structure/function. However, this substitution occurs at a position that is not conserved, and missense variants in nearby residues have not been reported in the Human Gene Mutation Database in association with COL6A2-related disorders (Stenson et al., 2014). -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 04, 2016	- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Apr 01, 2018

- -

Myosclerosis

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

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. -

Bethlem myopathy 1A

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

COL6A2-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 09, 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

0.10

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.10

Cadd

Benign

Dann

Benign

0.64

DEOGEN2

Uncertain

0.72

D;.;.;.

Eigen

Benign

-0.35

Eigen_PC

Benign

-0.42

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.83

T;T;.;T

M_CAP

Pathogenic

0.56

MetaRNN

Benign

0.038

T;T;T;T

MetaSVM

Uncertain

0.53

MutationAssessor

Uncertain

2.3

M;M;M;M

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Benign

0.39

PROVEAN

Pathogenic

-5.3

D;D;D;D

REVEL

Uncertain

0.40

Sift

Uncertain

0.0030

D;D;D;D

Sift4G

Uncertain

0.021

D;D;D;D

Polyphen

0.81

P;B;B;P

Vest4

0.36

MVP

0.94

MPC

0.49

ClinPred

0.095

GERP RS

2.6

Varity_R

0.48

gMVP

0.28

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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