X-40591254-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_ModerateBP6_Very_StrongBP7BS2

The NM_005765.3(ATP6AP2):c.189C>T(p.Leu63Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000486 in 1,208,683 control chromosomes in the GnomAD database, including 2 homozygotes. There are 166 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0023 ( 1 hom., 77 hem., cov: 23)

Exomes 𝑓: 0.00030 ( 1 hom. 89 hem. )

Consequence

ATP6AP2
NM_005765.3 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -0.737

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

ATP6AP2-related disorder
Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
congenital disorder of glycosylation, type IIr
Inheritance: AR, XL Classification: STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae)
syndromic X-linked intellectual disability Hedera type
Inheritance: XL Classification: STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: Orphanet, Ambry Genetics, G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
X-linked parkinsonism-spasticity syndrome
Inheritance: XL, Unknown Classification: MODERATE, SUPPORTIVE, LIMITED Submitted by: Orphanet, Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)

ATP6AP2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -15 ACMG points.

BP4

Computational evidence support a benign effect (REVEL=0.084).

BP6

Variant X-40591254-C-T is Benign according to our data. Variant chrX-40591254-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 136463.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.737 with no splicing effect.

BS2

High Hemizygotes in GnomAd4 at 77 XL,AR,Unknown gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP6AP2	NM_005765.3 link	c.189C>T	p.Leu63Leu	synonymous_variant	Exon 3 of 9	ENST00000636580.2	NP_005756.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP6AP2	ENST00000636580.2 link	c.189C>T	p.Leu63Leu	synonymous_variant	Exon 3 of 9	1	NM_005765.3	ENSP00000490083.1

Frequencies

GnomAD3 genomes

AF:

0.00229

AC:

256

AN:

111923

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00789

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000571

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000369

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000564

Gnomad OTH

AF:

0.00200

GnomAD2 exomes

AF:

0.000638

AC:

117

AN:

183379

AF XY:

0.000501

show subpopulations

Gnomad AFR exome

AF:

0.00828

Gnomad AMR exome

AF:

0.000219

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000122

Gnomad OTH exome

AF:

0.000221

GnomAD4 exome

AF:

0.000302

AC:

331

AN:

1096708

Hom.:

Cov.:

AF XY:

0.000245

AC XY:

AN XY:

362984

show subpopulations

African (AFR)

AF:

0.0107

AC:

281

AN:

26355

American (AMR)

AF:

0.000199

AC:

AN:

35204

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19385

East Asian (EAS)

AF:

0.00

AC:

AN:

30197

South Asian (SAS)

AF:

0.0000370

AC:

AN:

54091

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40520

Middle Eastern (MID)

AF:

0.000337

AC:

AN:

2968

European-Non Finnish (NFE)

AF:

0.0000119

AC:

AN:

842007

Other (OTH)

AF:

0.000652

AC:

AN:

45981

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.00229

AC:

256

AN:

111975

Hom.:

Cov.:

AF XY:

0.00225

AC XY:

AN XY:

34153

show subpopulations

African (AFR)

AF:

0.00787

AC:

243

AN:

30859

American (AMR)

AF:

0.000570

AC:

AN:

10519

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2656

East Asian (EAS)

AF:

0.00

AC:

AN:

3579

South Asian (SAS)

AF:

0.000370

AC:

AN:

2704

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6052

Middle Eastern (MID)

AF:

0.00

AC:

AN:

216

European-Non Finnish (NFE)

AF:

0.0000564

AC:

AN:

53186

Other (OTH)

AF:

0.00198

AC:

AN:

1517

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.00156

Hom.:

Bravo

AF:

0.00282

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Dec 09, 2013

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. -

Oct 18, 2016

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 26, 2017

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:3

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

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Syndromic X-linked intellectual disability Hedera type

Benign:1

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

History of neurodevelopmental disorder

Benign:1

Oct 04, 2012

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: 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

BayesDel_noAF

Benign

-0.54

CADD

Benign

1.1

(source)

DANN

Benign

0.76

PhyloP100

-0.74

PromoterAI

0.0014

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=286/14

polymorphism (auto)

(source)

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

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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