chr21-46126066-G-A

Position:

chr21-46126066-G-A

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM1BP4_ModerateBP6

The NM_001849.4(COL6A2):c.2251G>A(p.Asp751Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000924 in 1,612,870 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000098 ( 0 hom. )

Consequence

COL6A2
NM_001849.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:1

Conservation

PhyloP100: 2.46

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 -1 ACMG points.

PM1

In a domain VWFA 2 (size 190) in uniprot entity CO6A2_HUMAN there are 17 pathogenic changes around while only 5 benign (77%) in NM_001849.4

BP4

Computational evidence support a benign effect (MetaRNN=0.19104952).

BP6

Variant 21-46126066-G-A is Benign according to our data. Variant chr21-46126066-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 288586.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL6A2	NM_001849.4 linkuse as main transcript	c.2251G>A	p.Asp751Asn	missense_variant	26/28	ENST00000300527.9	NP_001840.3	P12110-1A0A384MDP3
COL6A2	NM_058174.3 linkuse as main transcript	c.2251G>A	p.Asp751Asn	missense_variant	26/28		NP_478054.2	P12110-2
COL6A2	NM_058175.3 linkuse as main transcript	c.2251G>A	p.Asp751Asn	missense_variant	26/28		NP_478055.2	P12110-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
COL6A2	ENST00000300527.9 linkuse as main transcript	c.2251G>A	p.Asp751Asn	missense_variant	26/28	1	NM_001849.4	ENSP00000300527.4	P12110-1
COL6A2	ENST00000397763.6 linkuse as main transcript	c.2251G>A	p.Asp751Asn	missense_variant	26/28	5		ENSP00000380870.1	P12110-2
COL6A2	ENST00000409416.6 linkuse as main transcript	c.2251G>A	p.Asp751Asn	missense_variant	25/27	5		ENSP00000387115.1	P12110-3

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000279

AC:

AN:

250838

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135762

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000530

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000979

AC:

143

AN:

1460676

Hom.:

Cov.:

AF XY:

0.0000922

AC XY:

AN XY:

726662

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

0.000124

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152194

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74350

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000386

Hom.:

Bravo

AF:

0.0000416

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000577

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jun 07, 2016

- -

Ullrich congenital muscular dystrophy 1A;C1850671:Myosclerosis;CN029274:Bethlem myopathy 1A

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

COL6A2-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 30, 2024

The COL6A2 c.2251G>A variant is predicted to result in the amino acid substitution p.Asp751Asn. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0053% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Bethlem myopathy 1A

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 17, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.072

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.46

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.17

T;.;.;.

Eigen

Benign

-0.76

Eigen_PC

Benign

-0.71

FATHMM_MKL

Benign

0.57

LIST_S2

Uncertain

0.89

D;D;.;D

M_CAP

Benign

0.073

MetaRNN

Benign

0.19

T;T;T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

-0.060

N;N;N;N

PrimateAI

Benign

0.45

PROVEAN

Benign

-0.56

N;N;N;N

REVEL

Benign

0.15

Sift

Benign

0.24

T;T;T;T

Sift4G

Benign

0.78

T;T;T;T

Polyphen

0.73

P;B;B;B

Vest4

0.50

MVP

0.76

MPC

0.31

ClinPred

0.30

GERP RS

3.0

Varity_R

0.099

gMVP

0.70

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