rs17883456

Variant names:

Variant summary

Our verdict is Benign. The variant received -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 (★★). Synonymous variant affecting the same amino acid position (i.e. A813A) has been classified as Likely 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

Publications

20 publications found

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 Gene-Disease associations (from GenCC):

wrinkly skin syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Genomics England PanelApp
autosomal recessive cutis laxa type 2, classic type
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Genomics England PanelApp, Orphanet
autosomal recessive cutis laxa type 2A
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

ATP6V0A2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

PP3

Multiple lines of computational evidence support a deleterious effect 8: AlphaMissense, Cadd, Dann, Eigen, MutationAssessor, phyloP100way_vertebrate, REVEL, 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 VariationId is 95521.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 rank	MANE	Protein	UniProt
ATP6V0A2	NM_012463.4 link	c.2438C>T	p.Ala813Val	missense_variant	Exon 19 of 20	ENST00000330342.8	NP_036595.2	Q9Y487
ATP6V0A2	XM_024448910.2 link	c.2318C>T	p.Ala773Val	missense_variant	Exon 18 of 19		XP_024304678.1
ATP6V0A2	XM_024448911.2 link	c.1925C>T	p.Ala642Val	missense_variant	Exon 15 of 16		XP_024304679.1
ATP6V0A2	XM_024448912.2 link	c.1616C>T	p.Ala539Val	missense_variant	Exon 12 of 13		XP_024304680.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP6V0A2	ENST00000330342.8 link	c.2438C>T	p.Ala813Val	missense_variant	Exon 19 of 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

GnomAD2 exomes

AF:

0.0282

AC:

7088

AN:

251488

AF XY:

0.0289

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 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

African (AFR)

AF:

0.00705

AC:

236

AN:

33480

American (AMR)

AF:

0.0174

AC:

776

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0574

AC:

1501

AN:

26136

East Asian (EAS)

AF:

0.000202

AC:

AN:

39700

South Asian (SAS)

AF:

0.0186

AC:

1606

AN:

86258

European-Finnish (FIN)

AF:

0.0411

AC:

2194

AN:

53406

Middle Eastern (MID)

AF:

0.0593

AC:

342

AN:

5768

European-Non Finnish (NFE)

AF:

0.0349

AC:

38774

AN:

1112004

Other (OTH)

AF:

0.0320

AC:

1931

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

2668

5336

8003

10671

13339

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1426

2852

4278

5704

7130

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0250

AC:

3814

AN:

152300

Hom.:

Cov.:

AF XY:

0.0248

AC XY:

1850

AN XY:

74468

show subpopulations

African (AFR)

AF:

0.00700

AC:

291

AN:

41570

American (AMR)

AF:

0.0173

AC:

265

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.0499

AC:

173

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5188

South Asian (SAS)

AF:

0.0172

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0407

AC:

432

AN:

10606

Middle Eastern (MID)

AF:

0.0612

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0365

AC:

2481

AN:

68030

Other (OTH)

AF:

0.0317

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

190

380

569

759

949

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

150

200

250

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0325

Hom.:

334

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

Oct 02, 2013

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 22, 2016

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

May 31, 2018

SIB Swiss Institute of Bioinformatics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:curation

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. -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

ALG9 congenital disorder of glycosylation

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cutis laxa with osteodystrophy

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

(source)

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;.;.

PhyloP100

7.9

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

Mutation Taster

=28/72

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over