rs142880107

Positions:

chr21-46118635-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1PP3_ModerateBP6

The NM_001849.4(COL6A2):c.1138C>T(p.Arg380Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000143 in 1,612,530 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. R380H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 34)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

COL6A2
NM_001849.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 2.55

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 Uncertain_significance. Variant got 3 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 9 uncertain in NM_001849.4

PP3

MetaRNN computational evidence supports a deleterious effect, 0.906

BP6

Variant 21-46118635-C-T is Benign according to our data. Variant chr21-46118635-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 542974.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
COL6A2	NM_001849.4 linkuse as main transcript	c.1138C>T	p.Arg380Cys	missense_variant	13/28	ENST00000300527.9
COL6A2	NM_058174.3 linkuse as main transcript	c.1138C>T	p.Arg380Cys	missense_variant	13/28	ENST00000397763.6
COL6A2	NM_058175.3 linkuse as main transcript	c.1138C>T	p.Arg380Cys	missense_variant	13/28

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL6A2	ENST00000300527.9 linkuse as main transcript	c.1138C>T	p.Arg380Cys	missense_variant	13/28	1	NM_001849.4	P1	P12110-1
COL6A2	ENST00000397763.6 linkuse as main transcript	c.1138C>T	p.Arg380Cys	missense_variant	13/28	5	NM_058174.3		P12110-2
COL6A2	ENST00000409416.6 linkuse as main transcript	c.1138C>T	p.Arg380Cys	missense_variant	12/27	5			P12110-3

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152232

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000162

AC:

AN:

247530

Hom.:

AF XY:

0.0000223

AC XY:

AN XY:

134554

show subpopulations

Gnomad AFR exome

AF:

0.000127

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000328

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000898

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000110

AC:

AN:

1460180

Hom.:

Cov.:

AF XY:

0.00000964

AC XY:

AN XY:

726362

show subpopulations

Gnomad4 AFR exome

AF:

0.000119

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000630

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000459

AC:

AN:

152350

Hom.:

Cov.:

AF XY:

0.0000537

AC XY:

AN XY:

74502

show subpopulations

Gnomad4 AFR

AF:

0.000144

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000453

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000248

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Oct 24, 2019

In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Reported previously in a patient with leg weakness and atrophy with sparing of the quadriceps, bilateral foot drop, scapular winging, hand weakness and atrophy, abnormal EMG, and severe contractures. However, this patient and his affected brother were also found to be compound heterozygous for two variants in the GNE gene, and authors concluded their clinical presentation was consistent with GNE myopathy (Dotti et al., 2018); This variant is associated with the following publications: (PMID: 29406958) -

Bethlem myopathy 1A

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jun 03, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.56

BayesDel_addAF

Uncertain

0.035

BayesDel_noAF

Uncertain

0.050

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.67

D;.;.;.

Eigen

Uncertain

0.64

Eigen_PC

Uncertain

0.60

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.89

D;D;.;D

M_CAP

Pathogenic

0.76

MetaRNN

Pathogenic

0.91

D;D;D;D

MetaSVM

Pathogenic

0.91

MutationAssessor

Uncertain

2.6

M;M;M;M

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Uncertain

0.70

PROVEAN

Uncertain

-3.9

D;D;D;D

REVEL

Pathogenic

0.77

Sift

Uncertain

0.0030

D;D;D;D

Sift4G

Uncertain

0.013

D;D;D;D

Polyphen

1.0

D;D;D;D

Vest4

0.71

MVP

0.93

MPC

0.71

ClinPred

0.90

GERP RS

4.7

Varity_R

0.42

gMVP

0.56

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