rs74922060

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_012463.4(ATP6V0A2):c.1016G>A(p.Arg339His) variant causes a missense change. The variant allele was found at a frequency of 0.00668 in 1,614,096 control chromosomes in the GnomAD database, including 243 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.022 ( 105 hom., cov: 32)

Exomes 𝑓: 0.0050 ( 138 hom. )

Consequence

ATP6V0A2
NM_012463.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 5.95

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0037205517).

BP6

Variant 12-123737249-G-A is Benign according to our data. Variant chr12-123737249-G-A is described in ClinVar as [Benign]. Clinvar id is 95516.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-123737249-G-A is described in Lovd as [Benign]. Variant chr12-123737249-G-A is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0536 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.1016G>A	p.Arg339His	missense_variant	9/20	ENST00000330342.8	NP_036595.2	Q9Y487
ATP6V0A2	XM_024448910.2 linkuse as main transcript	c.1016G>A	p.Arg339His	missense_variant	9/19		XP_024304678.1
ATP6V0A2	XM_024448911.2 linkuse as main transcript	c.503G>A	p.Arg168His	missense_variant	5/16		XP_024304679.1
ATP6V0A2	XM_024448912.2 linkuse as main transcript	c.194G>A	p.Arg65His	missense_variant	2/13		XP_024304680.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATP6V0A2	ENST00000330342.8 linkuse as main transcript	c.1016G>A	p.Arg339His	missense_variant	9/20	1	NM_012463.4	ENSP00000332247.2		Q9Y487

Frequencies

GnomAD3 genomes

AF:

0.0225

AC:

3420

AN:

152112

Hom.:

105

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0556

Gnomad AMI

AF:

0.0296

Gnomad AMR

AF:

0.0544

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00635

Gnomad SAS

AF:

0.00456

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00228

Gnomad OTH

AF:

0.0225

GnomAD3 exomes

AF:

0.0118

AC:

2959

AN:

251340

Hom.:

AF XY:

0.00978

AC XY:

1328

AN XY:

135854

show subpopulations

Gnomad AFR exome

AF:

0.0592

Gnomad AMR exome

AF:

0.0397

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00723

Gnomad SAS exome

AF:

0.00431

Gnomad FIN exome

AF:

0.000277

Gnomad NFE exome

AF:

0.00269

Gnomad OTH exome

AF:

0.00783

GnomAD4 exome

AF:

0.00503

AC:

7352

AN:

1461866

Hom.:

138

Cov.:

AF XY:

0.00479

AC XY:

3480

AN XY:

727236

show subpopulations

Gnomad4 AFR exome

AF:

0.0568

Gnomad4 AMR exome

AF:

0.0421

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00456

Gnomad4 SAS exome

AF:

0.00485

Gnomad4 FIN exome

AF:

0.000318

Gnomad4 NFE exome

AF:

0.00228

Gnomad4 OTH exome

AF:

0.00649

GnomAD4 genome

AF:

0.0225

AC:

3423

AN:

152230

Hom.:

105

Cov.:

AF XY:

0.0235

AC XY:

1748

AN XY:

74442

show subpopulations

Gnomad4 AFR

AF:

0.0555

Gnomad4 AMR

AF:

0.0544

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00637

Gnomad4 SAS

AF:

0.00436

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00228

Gnomad4 OTH

AF:

0.0223

Alfa

AF:

0.00651

Hom.:

Bravo

AF:

0.0271

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.00285

AC:

ESP6500AA

AF:

0.0572

AC:

252

ESP6500EA

AF:

0.00209

AC:

ExAC

AF:

0.0106

AC:

1288

Asia WGS

AF:

0.0110

AC:

AN:

3478

EpiCase

AF:

0.00191

EpiControl

AF:

0.00302

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 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. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 10, 2012	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not provided

Benign:3

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jun 05, 2015	- -
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

Benign

0.091

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.17

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.44

T;.;D

Eigen

Benign

0.16

Eigen_PC

Benign

0.061

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.93

D;D;D

MetaRNN

Benign

0.0037

T;T;T

MetaSVM

Uncertain

-0.17

MutationAssessor

Uncertain

2.6

M;.;.

PrimateAI

Benign

0.39

PROVEAN

Benign

-1.4

N;.;N

REVEL

Uncertain

0.52

Sift

Benign

0.032

D;.;D

Sift4G

Uncertain

0.035

D;D;D

Polyphen

0.72

P;D;.

Vest4

0.58

MPC

0.73

ClinPred

0.033

GERP RS

3.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.14

gMVP

0.79

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