PIK3C2A
protein-codingphosphatidylinositol-4-phosphate 3-kinase catalytic subunit type 2 alpha, the group of Phosphatidylinositol 3-kinase subunits
Gene summary
The protein encoded by this gene belongs to the phosphoinositide 3-kinase (PI3K) family. PI3-kinases play roles in signaling pathways involved in cell proliferation, oncogenic transformation, cell survival, cell migration, and intracellular protein trafficking. This protein contains a lipid kinase catalytic domain as well as a C-terminal C2 domain, a characteristic of class II PI3-kinases. C2 domains act as calcium-dependent phospholipid binding motifs that mediate translocation of proteins to membranes, and may also mediate protein-protein interactions. The PI3-kinase activity of this protein is not sensitive to nanomolar levels of the inhibitor wortmanin. This protein was shown to be able to be activated by insulin and may be involved in integrin-dependent signaling. [provided by RefSeq, Jul 2008]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~130.3 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0034145
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0034145
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0034145
Submitter: PanelApp Australia
Clinical Genomic Database (CGD)
Manifestation: Audiologic/Otolaryngologic; Craniofacial; Endocrine; Musculoskeletal; Neurologic; Ophthalmologic
Intervention: Audiologic/Otolaryngologic; Ophthalmologic
Rationale: Early recognition and treatment of hearing impairment may improve outcomes, including speech and language development; The condition can include secondary glaucoma, and awareness may allow prompt diagnosis and management
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to PIK3C2A variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_002645.4. 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 | 6 | 126 | 11 | 143 | ||
| missense | 1 | 284 | 20 | 6 | 311 | |
| nonsense | 11 | 2 | 2 | 15 | ||
| start loss | 0 | |||||
| frameshift | 8 | 2 | 10 | |||
| splice donor/acceptor (+/-2bp) | 6 | 8 | 14 | |||
| Total | 20 | 10 | 300 | 146 | 17 | 493 |
Highest pathogenic variant AF is 0.000009774701
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_002636.2 | 32 | MANE Select | |
| Ensembl | ENSP00000509400.1 | 32 | MANE Select | |
| RefSeq | NP_001308307.1 | 32 | Standard | |
| RefSeq | NP_001308309.1 | 31 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| pik3c2a | Danio rerio | Structure: intersegmental vessel Quality: process quality abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Inositol phosphate metabolism - Homo sapiens (human)
- Phosphatidylinositol signaling system - Homo sapiens (human)
- Proton Pump Inhibitor Pathway, Pharmacodynamics
- Anti-diabetic Drug Potassium Channel Inhibitors Pathway, Pharmacodynamics
- Sorafenib Pharmacodynamics
Biological Process
- phosphatidylinositol biosynthetic process
- exocytosis
- endocytosis
- epidermal growth factor receptor signaling pathway
- insulin receptor signaling pathway
Molecular Function
- ATP binding
- 1-phosphatidylinositol-3-kinase activity
- phosphatidylinositol 3-kinase activity
- 1-phosphatidylinositol-4-phosphate 3-kinase activity
- phosphatidylinositol binding
Cellular Component
- nucleus
- cytoplasm
- Golgi apparatus
- cytosol
- plasma membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000265970
- Coding exons
- 32
- Length
- 130254
- Individuals with no LoFs
- 125696
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 50
- Defined
- 125746
- p
- 0.000199
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 1.30 | 749 | 856 | 0.875 | 0.0000422 | 11066 |
| Missense (PolyPhen) | 233 | 351.06 | 0.66371 | 4629 | ||
| Synonymous | 1.31 | 267 | 296 | 0.903 | 0.0000145 | 3174 |
| Loss of Function | 6.59 | 23 | 90.7 | 0.254 | 0.00000512 | 1094 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00012 | 0.00012 | rare |
| Latino/Admixed American | 0.000089 | 0.000087 | rare |
| Ashkenazi Jewish | 0.000099 | 0.000099 | rare |
| East Asian | 0.000054 | 0.000054 | rare |
| Finnish | 0.000093 | 0.000092 | rare |
| European (Non-Finnish) | 0.00033 | 0.00033 | rare |
| South Asian | 0.00013 | 0.00013 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Generates phosphatidylinositol 3-phosphate (PtdIns3P) and phosphatidylinositol 3,4-bisphosphate (PtdIns(3,4)P2) that act as second messengers. Has a role in several intracellular trafficking events. Functions in insulin signaling and secretion. Required for translocation of the glucose transporter SLC2A4/GLUT4 to the plasma membrane and glucose uptake in response to insulin- mediated RHOQ activation. Regulates insulin secretion through two different mechanisms: involved in glucose-induced insulin secretion downstream of insulin receptor in a pathway that involves AKT1 activation and TBC1D4/AS160 phosphorylation, and participates in the late step of insulin granule exocytosis probably in insulin granule fusion. Synthesizes PtdIns3P in response to insulin signaling. Functions in clathrin-coated endocytic vesicle formation and distribution. Regulates dynamin- independent endocytosis, probably by recruiting EEA1 to internalizing vesicles. In neurosecretory cells synthesizes PtdIns3P on large dense core vesicles. Participates in calcium induced contraction of vascular smooth muscle by regulating myosin light chain (MLC) phosphorylation through a mechanism involving Rho kinase-dependent phosphorylation of the MLCP-regulatory subunit MYPT1. May play a role in the EGF signaling cascade. May be involved in mitosis and UV-induced damage response. Required for maintenance of normal renal structure and function by supporting normal podocyte function. {ECO:0000269|PubMed:10766823, ECO:0000269|PubMed:10805725, ECO:0000269|PubMed:11239472, ECO:0000269|PubMed:12719431, ECO:0000269|PubMed:16215232, ECO:0000269|PubMed:21081650, ECO:0000269|PubMed:9337861}.;
Recessive Scores
- pRec
- 0.636
Intolerance Scores
- LoFtool
- 0.657
- RVIS EVS
- -1.48
- RVIS percentile EVS
- 3.72
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.988
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |