ATP6AP2
protein-codingATPase H+ transporting accessory protein 2
Gene summary
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]
- ATP6IP2
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~27.5 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: XL
Disease ID:MONDO:0010319
Submitter: Genomics England PanelApp
Inheritance Pattern: XL
Disease ID:MONDO:0010482
Submitter: Genomics England PanelApp
Inheritance Pattern: XL
Disease ID:MONDO:0100146
Submitter: ClinGen
Variants in the ATP6AP2 gene were first reported in relation to X-linked ATP6AP2-related disorder in 2005 (Ramser, et al., PMID: 15746149). The affected male individuals are characterized by global developmental delay, intellectual impairment, spasticity, seizures, infantile onset of liver failure, recurrent infections, and features of parkinsonism (rigidity, resting tremor, and bradykinesia). These phenotypes may not appear in all individuals. The age of onset and expressivity are also variable. Evidence supporting this gene-disease relationship includes case-level data and segregation data. ATP6AP2 variants have been reported in at least seven probands in six publications (PMID: 15746149, 23595882, 26467484, 29127204, 30125339, and 30985297). Noteworthy, three of the reported splicing variants lead to exon 4 skipping in the ATP6AP2 gene via mRNA studies (PMID: 15746149, 23595882, 26467484, and 30985297), although the affected individuals manifest variable phenotypes. The gene-disease association is also supported by animal models and in vitro rescue experiments (PMID: 26376863 and 30985297). Defects in the ATP6AP2 gene may result in 1) MRXSH (mental retardation, X-linked, syndromic, Hedera type), 2) Congenital disorder of glycosylation, type IIr, and 3) Parkinsonism with spasticity, X-linked (see OMIM). In summary, ATP6AP2 is definitively associated with X-linked ATP6AP2-related disorder. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on 9/14/20 (SOP Version 7).
Inheritance Pattern: XL
Disease ID:MONDO:0026765
Submitter: PanelApp Australia
Inheritance Pattern: XL
Disease ID:MONDO:0010482
Submitter: PanelApp Australia
Inheritance Pattern: XL
Disease ID:MONDO:0010319
Submitter: G2P
Inheritance Pattern: XL
Disease ID:MONDO:0010319
Submitter: Ambry Genetics
Inheritance Pattern: XL
Disease ID:MONDO:0010482
Submitter: Ambry Genetics
Inheritance Pattern: Unknown
Disease ID:MONDO:0010482
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: XL
Disease ID:MONDO:0010319
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: XL
Disease ID:MONDO:0026765
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: XL
Disease ID:MONDO:0010482
Submitter: Orphanet
Inheritance Pattern: XL
Disease ID:MONDO:0010319
Submitter: Orphanet
Inheritance Pattern: XL
Disease ID:MONDO:0010319
Submitter: PanelApp Australia
Clinical Genomic Database (CGD)
Manifestation: Allergy/Immunology/Infectious; Gastrointestinal; Hematologic; Musculoskeletal; Neurologic
Intervention: Allergy/Immunology/Infectious; Hematologic; Neurologic
Rationale: In Parkinsonism, response to l-dopa has been reported; In Congenital disorder of glycosylation, type IIr, individuals have been described with recurrent infections, and awareness may allow early diagnosis and early and aggressive treatment of infections; In Congenital disorder of glycosylation, type IIr, awareness of coagulopathies may be beneficial in terms of medical management, especially in situations such as surgery
Comments: The evidence of variants being related to disease causation for some conditions has been questioned due to subsequent population-based studies
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to ATP6AP2 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_005765.3. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 2 | 19 | 50 | 2 | 73 | |
| missense | 1 | 2 | 153 | 11 | 1 | 168 |
| nonsense | 1 | 11 | 12 | |||
| start loss | 0 | |||||
| frameshift | 0 | |||||
| splice donor/acceptor (+/-2bp) | 21 | 1 | 22 | |||
| Total | 4 | 2 | 204 | 62 | 3 | 275 |
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_005756.2 | 9 | MANE Select | |
| Ensembl | ENSP00000490083.1 | 9 | MANE Select | |
| Ensembl | ENSP00000367697.5 | 9 | Standard | |
| Ensembl | ENSP00000367697.5 | 9 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| atp6ap2 | Danio rerio | Structure: enterocyte Quality: dilated abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Agents Acting on the Renin-Angiotensin System Pathway, Pharmacodynamics
- Renin-angiotensin system - Homo sapiens (human)
- ACE Inhibitor Pathway, Pharmacodynamics
- ACE Inhibitor Pathway
- Oxidative phosphorylation
Biological Process
- angiotensin maturation
- rostrocaudal neural tube patterning
- positive regulation of Wnt signaling pathway
- positive regulation of transforming growth factor beta1 production
- neutrophil degranulation
Molecular Function
- protein binding
- enzyme binding
- signaling receptor activity
Cellular Component
- plasma membrane
- external side of plasma membrane
- integral component of membrane
- neuron projection
- cell body
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000378438
- Coding exons
- 9
- Length
- 25744
- Individuals with no LoFs
- 0
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 0
- Defined
- 0
- p
- 0.00
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 1.66 | 84 | 139 | 0.603 | 0.0000108 | 2288 |
| Missense (PolyPhen) | 21 | 37.824 | 0.5552 | 724 | ||
| Synonymous | 0.689 | 43 | 49.1 | 0.875 | 0.00000365 | 695 |
| Loss of Function | 2.80 | 1 | 11.1 | 0.0903 | 7.70e-7 | 211 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0 | 0.0 | absent |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0 | 0.0 | absent |
| South Asian | 0 | 0.0 | absent |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Functions as a renin and prorenin cellular receptor. May mediate renin-dependent cellular responses by activating ERK1 and ERK2. By increasing the catalytic efficiency of renin in AGT/angiotensinogen conversion to angiotensin I, it may also play a role in the renin-angiotensin system (RAS). {ECO:0000269|PubMed:12045255}.;
- Disease
- DISEASE: Mental retardation, X-linked, with epilepsy (MRXE) [MIM:300423]: A disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. MRXE patients manifest mild to moderate mental retardation associated with epilepsy, delays in motor milestones and speech acquisition in infancy. {ECO:0000269|PubMed:15746149}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Parkinsonism with spasticity, X-linked (XPDS) [MIM:300911]: A syndrome characterized by parkinsonian features, such as cogwheel rigidity, resting tremor and bradykinesia, and variably penetrant spasticity. {ECO:0000269|PubMed:23595882}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.200
Intolerance Scores
- LoFtool
- 0.197
- RVIS EVS
- 0.13
- RVIS percentile EVS
- 63
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- E
- Essential (gene trap)
- E
- Indispensability pred.
- E
- Indispensability score
- 0.539
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |