X-40581084-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_005765.3(ATP6AP2):c.19C>T(p.Leu7Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000585 in 1,163,046 control chromosomes in the GnomAD database, including 1 homozygotes. There are 26 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L7V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 0 hem., cov: 25)

Exomes 𝑓: 0.000063 ( 1 hom. 26 hem. )

Consequence

ATP6AP2
NM_005765.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 0.0790

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

ATP6AP2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0450342).

BP6

Variant X-40581084-C-T is Benign according to our data. Variant chrX-40581084-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 204914.

BS2

High Hemizygotes in GnomAdExome4 at 26 XL,AR,Unknown gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005765.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP6AP2	NM_005765.3	MANE Select	c.19C>T	p.Leu7Phe	missense	Exon 1 of 9	NP_005756.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ATP6AP2	ENST00000636580.2	TSL:1 MANE Select	c.19C>T	p.Leu7Phe	missense	Exon 1 of 9	ENSP00000490083.1	O75787-1
ATP6AP2	ENST00000636639.1	TSL:1	n.19C>T		non_coding_transcript_exon	Exon 1 of 10	ENSP00000490382.1	A0A1B0GV60
ATP6AP2	ENST00000901377.1		c.19C>T	p.Leu7Phe	missense	Exon 1 of 9	ENSP00000571436.1

Frequencies

GnomAD3 genomes

AF:

0.0000177

AC:

AN:

113265

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000352

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000188

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000116

AC:

AN:

103160

AF XY:

0.000166

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000545

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000629

AC:

AN:

1049733

Hom.:

Cov.:

AF XY:

0.0000759

AC XY:

AN XY:

342645

show subpopulations

African (AFR)

AF:

0.0000405

AC:

AN:

24709

American (AMR)

AF:

0.00

AC:

AN:

27819

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18531

East Asian (EAS)

AF:

0.00

AC:

AN:

27013

South Asian (SAS)

AF:

0.000683

AC:

AN:

49767

European-Finnish (FIN)

AF:

0.00

AC:

AN:

36134

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3239

European-Non Finnish (NFE)

AF:

0.0000367

AC:

AN:

818355

Other (OTH)

AF:

0.0000226

AC:

AN:

44166

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

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

<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:

0.0000177

AC:

AN:

113313

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

35471

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31359

American (AMR)

AF:

0.00

AC:

AN:

10900

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2658

East Asian (EAS)

AF:

0.00

AC:

AN:

3547

South Asian (SAS)

AF:

0.000353

AC:

AN:

2835

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6295

Middle Eastern (MID)

AF:

0.00

AC:

AN:

215

European-Non Finnish (NFE)

AF:

0.0000188

AC:

AN:

53270

Other (OTH)

AF:

0.00

AC:

AN:

1554

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000869

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.000101

AC:

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Inborn genetic diseases (1)

not specified (1)

Syndromic X-linked intellectual disability Hedera type (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.054

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.64

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.10

FATHMM_MKL

Benign

0.067

LIST_S2

Benign

0.63

M_CAP

Uncertain

0.086

MetaRNN

Benign

0.045

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.14

PhyloP100

0.079

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-0.65

REVEL

Benign

0.048

Sift

Benign

0.13

Sift4G

Benign

0.34

Polyphen

0.0

Vest4

0.084

MutPred

0.26

Gain of sheet (P = 0.0221)

MVP

0.26

MPC

0.57

ClinPred

0.013

GERP RS

1.6

PromoterAI

0.017

Neutral

(source)

Varity_R

0.14

gMVP

0.60

Mutation Taster

=98/2

polymorphism

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over