rs35798522

chrX-40605570-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.14

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]

ACMG classification

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	UniProt
ATP6AP2	NM_005765.3	c.868G>C	p.Ala290Pro	missense_variant	9/9	ENST00000636580.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP6AP2	ENST00000636580.2	c.868G>C	p.Ala290Pro	missense_variant	9/9	1	NM_005765.3	P3

Frequencies

GnomAD3 genomes AF: 0.0185 AC: 2067 AN: 111919 Hom.: 47 Cov.: 23 AF XY: 0.0159 AC XY: 541 AN XY: 34113

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.: 21 AF XY: 0.00349 AC XY: 233 AN XY: 66788

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.: 47 Cov.: 29 AF XY: 0.00149 AC XY: 534 AN XY: 357479

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.: 47 Cov.: 23 AF XY: 0.0159 AC XY: 542 AN XY: 34174

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.: 47

Bravo AF: 0.0215

ESP6500AA AF: 0.0623 AC: 239

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00581 AC: 706

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

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. -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
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. -

Syndromic X-linked intellectual disability Hedera type Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

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. -

not provided Benign:1

Likely benign, no assertion criteria provided

clinical testing

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.73	T
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	N
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	T
MutationAssessor	Benign	-0.34	N;.;.;.;.;.;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	P;P;P;P
PrimateAI	Benign	0.19	T
Polyphen		0.25	B;.;B;.;.;.;.;.;.;.;B;.;.
MVP		0.54
MPC		0.68
ClinPred		0.0022	T
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

Other links and lift over

dbSNP: rs35798522; hg19: chrX-40464822;