X-40588995-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_005765.3(ATP6AP2):c.47G>A(p.Gly16Glu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: ATP6AP2 NM_005765.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.33

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATP6AP2	NM_005765.3	c.47G>A	p.Gly16Glu	missense_variant	2/9	ENST00000636580.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP6AP2	ENST00000636580.2	c.47G>A	p.Gly16Glu	missense_variant	2/9	1	NM_005765.3	P3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Syndromic X-linked intellectual disability Hedera type Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 14, 2021

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This sequence change replaces glycine with glutamic acid at codon 16 of the ATP6AP2 protein (p.Gly16Glu). The glycine residue is moderately conserved and there is a moderate physicochemical difference between glycine and glutamic acid. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with ATP6AP2-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Uncertain	0.059	T
BayesDel_noAF	Benign	-0.15
Cadd	Uncertain	25
Dann	Uncertain	0.99
DEOGEN2	Benign	0.25	T;.;T;.;.;T;.;T
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.89	D;D;D;D;D;D;D;D
M_CAP	Benign	0.076	D
MetaRNN	Uncertain	0.49	T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.16	T
MutationAssessor	Benign	1.8	L;L;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;N
PrimateAI	Uncertain	0.76	T
Polyphen		0.47	P;.;.;.;.;P;.;.
Vest4		0.66
MutPred		0.34		Loss of sheet (P = 0.0181);Loss of sheet (P = 0.0181);Loss of sheet (P = 0.0181);Loss of sheet (P = 0.0181);Loss of sheet (P = 0.0181);Loss of sheet (P = 0.0181);Loss of sheet (P = 0.0181);Loss of sheet (P = 0.0181);
MVP		0.61
MPC		1.7
ClinPred		0.97	D
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.68
gMVP		0.76

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: rs866274169; hg19: chrX-40448247;