X-40588981-T-C

Position:

chrX-40588981-T-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_005765.3(ATP6AP2):c.38-5T>C variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000431 in 1,206,348 control chromosomes in the GnomAD database, including 1 homozygotes. There are 132 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0023 ( 1 hom., 61 hem., cov: 23)

Exomes 𝑓: 0.00024 ( 0 hom. 71 hem. )

Consequence

ATP6AP2
NM_005765.3 splice_region, splice_polypyrimidine_tract, intron

Scores

Splicing: ADA: 0.0001392

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.0630

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 -16 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.81).

BP6

Variant X-40588981-T-C is Benign according to our data. Variant chrX-40588981-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 136465.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-40588981-T-C is described in Lovd as [Likely_benign].

BS2

High Hemizygotes in GnomAd4 at 61 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATP6AP2	NM_005765.3 linkuse as main transcript	c.38-5T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000636580.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP6AP2	ENST00000636580.2 linkuse as main transcript	c.38-5T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_005765.3	P3	O75787-1

Frequencies

GnomAD3 genomes

AF:

0.00229

AC:

256

AN:

111830

Hom.:

Cov.:

AF XY:

0.00179

AC XY:

AN XY:

33996

show subpopulations

Gnomad AFR

AF:

0.00804

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000479

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00267

GnomAD3 exomes

AF:

0.000633

AC:

116

AN:

183129

Hom.:

AF XY:

0.000399

AC XY:

AN XY:

67673

show subpopulations

Gnomad AFR exome

AF:

0.00801

Gnomad AMR exome

AF:

0.000365

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000122

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000241

AC:

264

AN:

1094464

Hom.:

Cov.:

AF XY:

0.000197

AC XY:

AN XY:

360390

show subpopulations

Gnomad4 AFR exome

AF:

0.00802

Gnomad4 AMR exome

AF:

0.000540

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000477

Gnomad4 OTH exome

AF:

0.000610

GnomAD4 genome

AF:

0.00229

AC:

256

AN:

111884

Hom.:

Cov.:

AF XY:

0.00179

AC XY:

AN XY:

34060

show subpopulations

Gnomad4 AFR

AF:

0.00802

Gnomad4 AMR

AF:

0.000478

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00264

Alfa

AF:

0.00169

Hom.:

Bravo

AF:

0.00289

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 29, 2016	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 26, 2013	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. -

Syndromic X-linked intellectual disability Hedera type

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 30, 2024

- -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Syndromic X-linked intellectual disability Hedera type;C3806722:X-linked parkinsonism-spasticity syndrome;C5393313:Congenital disorder of glycosylation, type IIr

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 14, 2021

- -

ATP6AP2-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 06, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

DANN

Benign

0.76

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00014

dbscSNV1_RF

Benign

0.010

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