PIK3CG
protein-codingphosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit gamma, the group of Phosphatidylinositol 3-kinase subunits
Gene summary
Phosphoinositide 3-kinases (PI3Ks) phosphorylate inositol lipids and are involved in the immune response. The protein encoded by this gene is a class I catalytic subunit of PI3K. Like other class I catalytic subunits (p110-alpha p110-beta, and p110-delta), the encoded protein binds a p85 regulatory subunit to form PI3K. This gene is located in a commonly deleted segment of chromosome 7 previously identified in myeloid leukemias. Several transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Jun 2015]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~43.7 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0030717
Submitter: ClinGen
*PIK3CG* was first reported in relation to immunodeficiency 97 with autoinflammation in 2019 (Takeda AJ, et al., 2019, PMID: 31554793) and a second patient reported in 2020 (Thian M, et al., 2020, PMID: 33054089). Each patient is compound heterozygous for partial to full loss of function variants, for a total of four variants (3 missense and one frameshift). *PIK3CG* encodes the p110γ catalytic subunit of PI3Kγ, which phosphorylates PtdIns(4,5)P2 to produce PtdIns(3,4,5)P3, a versatile second messenger that potently activates diverse signaling cascades to coordinate the cellular response to growth factors, cytokines, chemokines, and antigen receptor stimulation, among other inputs. Data are consistent with a mechanistic model in which deficiency in PI3Kγ results in GSK3-dependent overproduction of IL-12 and IL-23 by myeloid cells, leading to increased T cell accumulation in tissues that, together with defective immunoglobulin production and reduced regulatory T cells, underlies disease pathophysiology. Experimentally, this gene-disease relationship is supported by its increased expression in tissues involved in immune responses (PMID: 24014027) and function as a phosphatidylinositol 3-kinase (PMID: 24014027) which participates in T cell receptor–induced T cell activation (PMID: 17998387) which was observed in both patient and knock out cells (PMID: 33054089). Additionally, the defects in patient T cells are rescued with wild type protein (PMID: 33054089). Finally, multiple mouse models have been reported (PMID: 10669416, PMID: 31554793) that recapitulate the disease. In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged.
Inheritance Pattern: AR
Disease ID:MONDO:0030717
Submitter: PanelApp Australia
Inheritance Pattern: Unknown
Disease ID:MONDO:0030717
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0030717
Submitter: Ambry Genetics
Clinical Genomic Database (CGD)
Manifestation: Allergy/Immunology/Infectious
Intervention: Allergy/Immunology/Infectious
Rationale: Antiinfectious prophylaxis, early and aggressive treatment of infections, and medical management (eg, treatment with anakinra has been described) may be beneficial
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to PIK3CG variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_001282426.2. 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 | 4 | 18 | 2 | 24 | ||
| missense | 3 | 105 | 10 | 118 | ||
| nonsense | 2 | 4 | 6 | |||
| start loss | 0 | |||||
| frameshift | 6 | 6 | ||||
| splice donor/acceptor (+/-2bp) | 1 | 1 | ||||
| Total | 3 | 2 | 120 | 28 | 2 | 155 |
Highest pathogenic variant AF is 0.00005647288
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_001269355.1 | 10 | MANE Select | |
| Ensembl | ENSP00000419260.1 | 10 | MANE Select | |
| RefSeq | NP_001269356.1 | 10 | Standard | |
| RefSeq | NP_002640.2 | 10 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- PI3K-Akt signaling pathway - Homo sapiens (human)
- Platelet activation - Homo sapiens (human)
- Oxytocin signaling pathway - Homo sapiens (human)
- Kaposi,s sarcoma-associated herpesvirus infection - Homo sapiens (human)
- Inositol phosphate metabolism - Homo sapiens (human)
Biological Process
- angiogenesis
- cytokine production
- adaptive immune response
- dendritic cell chemotaxis
- positive regulation of acute inflammatory response
Molecular Function
- protein kinase activity
- protein serine/threonine kinase activity
- protein binding
- ATP binding
- kinase activity
Cellular Component
- cytoplasm
- cytosol
- plasma membrane
- phosphatidylinositol 3-kinase complex
- phosphatidylinositol 3-kinase complex, class IB
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000359195
- Coding exons
- 10
- Length
- 41868
- Individuals with no LoFs
- 125696
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 52
- Defined
- 125748
- p
- 0.000207
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 1.97 | 514 | 656 | 0.784 | 0.0000406 | 7276 |
| Missense (PolyPhen) | 120 | 203.12 | 0.59078 | 2312 | ||
| Synonymous | 0.115 | 273 | 275 | 0.991 | 0.0000197 | 2129 |
| Loss of Function | 3.72 | 18 | 44.9 | 0.401 | 0.00000216 | 514 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0.00012 | 0.00012 | rare |
| Ashkenazi Jewish | 0.000099 | 0.000099 | rare |
| East Asian | 0.00038 | 0.00027 | rare |
| Finnish | 0.00019 | 0.00018 | rare |
| European (Non-Finnish) | 0.00028 | 0.00027 | rare |
| South Asian | 0.00020 | 0.00020 | rare |
| Other | 0.00016 | 0.00016 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Phosphoinositide-3-kinase (PI3K) that phosphorylates PtdIns(4,5)P2 (Phosphatidylinositol 4,5-bisphosphate) to generate phosphatidylinositol 3,4,5-trisphosphate (PIP3). PIP3 plays a key role by recruiting PH domain-containing proteins to the membrane, including AKT1 and PDPK1, activating signaling cascades involved in cell growth, survival, proliferation, motility and morphology. Links G-protein coupled receptor activation to PIP3 production. Involved in immune, inflammatory and allergic responses. Modulates leukocyte chemotaxis to inflammatory sites and in response to chemoattractant agents. May control leukocyte polarization and migration by regulating the spatial accumulation of PIP3 and by regulating the organization of F-actin formation and integrin- based adhesion at the leading edge. Controls motility of dendritic cells. Together with PIK3CD is involved in natural killer (NK) cell development and migration towards the sites of inflammation. Participates in T-lymphocyte migration. Regulates T-lymphocyte proliferation and cytokine production. Together with PIK3CD participates in T-lymphocyte development. Required for B- lymphocyte development and signaling. Together with PIK3CD participates in neutrophil respiratory burst. Together with PIK3CD is involved in neutrophil chemotaxis and extravasation. Together with PIK3CB promotes platelet aggregation and thrombosis. Regulates alpha-IIb/beta-3 integrins (ITGA2B/ ITGB3) adhesive function in platelets downstream of P2Y12 through a lipid kinase activity-independent mechanism. May have also a lipid kinase activity-dependent function in platelet aggregation. Involved in endothelial progenitor cell migration. Negative regulator of cardiac contractility. Modulates cardiac contractility by anchoring protein kinase A (PKA) and PDE3B activation, reducing cAMP levels. Regulates cardiac contractility also by promoting beta-adrenergic receptor internalization by binding to GRK2 and by non-muscle tropomyosin phosphorylation. Also has serine/threonine protein kinase activity: both lipid and protein kinase activities are required for beta-adrenergic receptor endocytosis. May also have a scaffolding role in modulating cardiac contractility. Contributes to cardiac hypertrophy under pathological stress. Through simultaneous binding of PDE3B to RAPGEF3 and PIK3R6 is assembled in a signaling complex in which the PI3K gamma complex is activated by RAPGEF3 and which is involved in angiogenesis. {ECO:0000269|PubMed:12163475, ECO:0000269|PubMed:15294162, ECO:0000269|PubMed:16094730, ECO:0000269|PubMed:21393242, ECO:0000269|PubMed:7624799}.;
Recessive Scores
- pRec
- 0.760
Intolerance Scores
- LoFtool
- 0.490
- RVIS EVS
- -0.81
- RVIS percentile EVS
- 12.05
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.997
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |