rs17883456

Positions:

chr12-123756959-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP3BP4_StrongBP6_Very_StrongBA1

The NM_012463.4(ATP6V0A2):c.2438C>T(p.Ala813Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0317 in 1,614,172 control chromosomes in the GnomAD database, including 968 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.025 ( 79 hom., cov: 31)

Exomes 𝑓: 0.032 ( 889 hom. )

Consequence

ATP6V0A2
NM_012463.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 7.91

Variant links:

Genes affected

ATP6V0A2 (HGNC:18481): (ATPase H+ transporting V0 subunit a2) The protein encoded by this gene is a subunit of the vacuolar ATPase (v-ATPase), an heteromultimeric enzyme that is present in intracellular vesicles and in the plasma membrane of specialized cells, and which is essential for the acidification of diverse cellular components. V-ATPase is comprised of a membrane peripheral V(1) domain for ATP hydrolysis, and an integral membrane V(0) domain for proton translocation. The subunit encoded by this gene is a component of the V(0) domain. Mutations in this gene are a cause of both cutis laxa type II and wrinkly skin syndrome. [provided by RefSeq, Jul 2009]

ATP6V0A2 links:

ATP6V0A2 (HGNC:):

ATP6V0A2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

PP3

Multiple lines of computational evidence support a deleterious effect 7: AlphaMissense, Cadd, Dann, Eigen, MutationAssessor, phyloP100way_vertebrate, REVEL [when BayesDel_addAF, max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.0110394955).

BP6

Variant 12-123756959-C-T is Benign according to our data. Variant chr12-123756959-C-T is described in ClinVar as [Benign]. Clinvar id is 95521.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-123756959-C-T is described in Lovd as [Benign]. Variant chr12-123756959-C-T is described in Lovd as [Likely_benign].

BA1

GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0541 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATP6V0A2	NM_012463.4 linkuse as main transcript	c.2438C>T	p.Ala813Val	missense_variant	19/20	ENST00000330342.8	NP_036595.2	Q9Y487
ATP6V0A2	XM_024448910.2 linkuse as main transcript	c.2318C>T	p.Ala773Val	missense_variant	18/19		XP_024304678.1
ATP6V0A2	XM_024448911.2 linkuse as main transcript	c.1925C>T	p.Ala642Val	missense_variant	15/16		XP_024304679.1
ATP6V0A2	XM_024448912.2 linkuse as main transcript	c.1616C>T	p.Ala539Val	missense_variant	12/13		XP_024304680.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATP6V0A2	ENST00000330342.8 linkuse as main transcript	c.2438C>T	p.Ala813Val	missense_variant	19/20	1	NM_012463.4	ENSP00000332247.2		Q9Y487

Frequencies

GnomAD3 genomes

AF:

0.0251

AC:

3819

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00702

Gnomad AMI

AF:

0.00329

Gnomad AMR

AF:

0.0174

Gnomad ASJ

AF:

0.0499

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.0178

Gnomad FIN

AF:

0.0407

Gnomad MID

AF:

0.0570

Gnomad NFE

AF:

0.0365

Gnomad OTH

AF:

0.0320

GnomAD3 exomes

AF:

0.0282

AC:

7088

AN:

251488

Hom.:

156

AF XY:

0.0289

AC XY:

3930

AN XY:

135920

show subpopulations

Gnomad AFR exome

AF:

0.00621

Gnomad AMR exome

AF:

0.0169

Gnomad ASJ exome

AF:

0.0573

Gnomad EAS exome

AF:

0.000217

Gnomad SAS exome

AF:

0.0179

Gnomad FIN exome

AF:

0.0414

Gnomad NFE exome

AF:

0.0366

Gnomad OTH exome

AF:

0.0350

GnomAD4 exome

AF:

0.0324

AC:

47368

AN:

1461872

Hom.:

889

Cov.:

AF XY:

0.0322

AC XY:

23386

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.00705

Gnomad4 AMR exome

AF:

0.0174

Gnomad4 ASJ exome

AF:

0.0574

Gnomad4 EAS exome

AF:

0.000202

Gnomad4 SAS exome

AF:

0.0186

Gnomad4 FIN exome

AF:

0.0411

Gnomad4 NFE exome

AF:

0.0349

Gnomad4 OTH exome

AF:

0.0320

GnomAD4 genome

AF:

0.0250

AC:

3814

AN:

152300

Hom.:

Cov.:

AF XY:

0.0248

AC XY:

1850

AN XY:

74468

show subpopulations

Gnomad4 AFR

AF:

0.00700

Gnomad4 AMR

AF:

0.0173

Gnomad4 ASJ

AF:

0.0499

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.0172

Gnomad4 FIN

AF:

0.0407

Gnomad4 NFE

AF:

0.0365

Gnomad4 OTH

AF:

0.0317

Alfa

AF:

0.0337

Hom.:

172

Bravo

AF:

0.0227

TwinsUK

AF:

0.0375

AC:

139

ALSPAC

AF:

0.0335

AC:

129

ESP6500AA

AF:

0.00749

AC:

ESP6500EA

AF:

0.0352

AC:

303

ExAC

AF:

0.0284

AC:

3442

Asia WGS

AF:

0.00953

AC:

AN:

3478

EpiCase

AF:

0.0356

EpiControl

AF:

0.0355

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	May 31, 2018	This variant is interpreted as a Benign - Stand Alone. The following ACMG Tag(s) were applied: BA1 => Allele frequency is >5% in gnomAD (Ashkenazi Jewish population) and about 3% in other populations in Exome Aggregation Consortium. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 02, 2013	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 22, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

ALG9 congenital disorder of glycosylation

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Cutis laxa with osteodystrophy

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.94

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Uncertain

0.070

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.66

D;.;D

Eigen

Pathogenic

0.95

Eigen_PC

Pathogenic

0.88

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

D;D;D

MetaRNN

Benign

0.011

T;T;T

MetaSVM

Uncertain

0.42

MutationAssessor

Pathogenic

3.9

H;.;.

PrimateAI

Uncertain

0.72

PROVEAN

Uncertain

-3.7

D;D;D

REVEL

Pathogenic

0.71

Sift

Uncertain

0.0050

D;D;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

D;.;.

Vest4

0.93

MPC

0.68

ClinPred

0.071

GERP RS

5.7

Varity_R

0.53

gMVP

0.74

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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