X-40605570-G-C

Position:

chrX-40605570-G-C

Variant summary

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

The NM_005765.3(ATP6AP2):c.868G>C(p.Ala290Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00348 in 1,202,773 control chromosomes in the GnomAD database, including 94 homozygotes. There are 1,076 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.018 ( 47 hom., 542 hem., cov: 23)

Exomes 𝑓: 0.0019 ( 47 hom. 534 hem. )

Consequence

ATP6AP2
NM_005765.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 1.14

Variant links:

Genes affected

ATP6AP2 (HGNC:18305): (ATPase H+ transporting accessory protein 2) This gene encodes a protein that is associated with adenosine triphosphatases (ATPases). Proton-translocating ATPases have fundamental roles in energy conservation, secondary active transport, acidification of intracellular compartments, and cellular pH homeostasis. There are three classes of ATPases- F, P, and V. The vacuolar (V-type) ATPases have a transmembrane proton-conducting sector and an extramembrane catalytic sector. The encoded protein has been found associated with the transmembrane sector of the V-type ATPases. [provided by RefSeq, Jul 2008]

ATP6AP2 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=0.0016251802).

BP6

Variant X-40605570-G-C is Benign according to our data. Variant chrX-40605570-G-C is described in ClinVar as [Benign]. Clinvar id is 128487.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-40605570-G-C is described in Lovd as [Benign]. Variant chrX-40605570-G-C is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.062 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATP6AP2	NM_005765.3 linkuse as main transcript	c.868G>C	p.Ala290Pro	missense_variant	9/9	ENST00000636580.2	NP_005756.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATP6AP2	ENST00000636580.2 linkuse as main transcript	c.868G>C	p.Ala290Pro	missense_variant	9/9	1	NM_005765.3	ENSP00000490083	P3	O75787-1

Frequencies

GnomAD3 genomes

AF:

0.0185

AC:

2067

AN:

111919

Hom.:

Cov.:

AF XY:

0.0159

AC XY:

541

AN XY:

34113

show subpopulations

Gnomad AFR

AF:

0.0644

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00571

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000732

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000940

Gnomad OTH

AF:

0.0140

GnomAD3 exomes

AF:

0.00532

AC:

968

AN:

181960

Hom.:

AF XY:

0.00349

AC XY:

233

AN XY:

66788

show subpopulations

Gnomad AFR exome

AF:

0.0656

Gnomad AMR exome

AF:

0.00322

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000158

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000110

Gnomad OTH exome

AF:

0.00223

GnomAD4 exome

AF:

0.00194

AC:

2112

AN:

1090803

Hom.:

Cov.:

AF XY:

0.00149

AC XY:

534

AN XY:

357479

show subpopulations

Gnomad4 AFR exome

AF:

0.0667

Gnomad4 AMR exome

AF:

0.00341

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000222

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000431

Gnomad4 OTH exome

AF:

0.00395

GnomAD4 genome

AF:

0.0185

AC:

2069

AN:

111970

Hom.:

Cov.:

AF XY:

0.0159

AC XY:

542

AN XY:

34174

show subpopulations

Gnomad4 AFR

AF:

0.0643

Gnomad4 AMR

AF:

0.00570

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000734

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000940

Gnomad4 OTH

AF:

0.0138

Alfa

AF:

0.00980

Hom.:

Bravo

AF:

0.0215

ESP6500AA

AF:

0.0623

AC:

239

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00581

AC:

706

EpiCase

AF:

0.000109

EpiControl

AF:

0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 03, 2012	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. -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Syndromic X-linked intellectual disability Hedera type

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 16, 2015

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.73

BayesDel_noAF

Benign

-0.77

CADD

Benign

4.4

DANN

Benign

0.79

DEOGEN2

Benign

0.053

T;.;T;T;T;.;T;.;T;T;T;.;T

FATHMM_MKL

Benign

0.15

LIST_S2

Benign

0.70

T;T;T;T;T;T;T;T;T;T;T;T;T

MetaRNN

Benign

0.0016

T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.34

N;.;.;.;.;.;.;.;.;.;.;.;.

MutationTaster

Benign

1.0

P;P;P;P

PrimateAI

Benign

0.19

REVEL

Benign

0.084

Polyphen

0.25

B;.;B;.;.;.;.;.;.;.;B;.;.

MVP

0.54

MPC

0.68

ClinPred

0.0022

GERP RS

-8.4

Varity_R

0.13

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