PIK3R2
phosphoinositide-3-kinase regulatory subunit 2, the group of SH2 domain containing
Basic information
Region (hg38): 19:18153162-18170532
Links
Phenotypes
GenCC
Source:
- megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 1 (Definitive), mode of inheritance: AD
- megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 1 (Strong), mode of inheritance: AD
- megalencephaly-polymicrogyria-postaxial polydactyly-hydrocephalus syndrome (Supportive), mode of inheritance: AD
- megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 1 (Strong), mode of inheritance: AD
- megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 1 (Definitive), mode of inheritance: AD
- overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes (Definitive), mode of inheritance: AD
Clinical Genomic Database
Source:
| Condition | Inheritance | Intervention Categories | Intervention/Rationale | Manifestation Categories | References |
|---|---|---|---|---|---|
| Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 1 | AD | General | Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing | Craniofacial; Musculoskeletal; Neurologic | 17675034; 22729224; 23745724 |
ClinVar
This is a list of variants' phenotypes submitted to
- Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 1 (235 variants)
- not provided (126 variants)
- Inborn genetic diseases (39 variants)
- not specified (17 variants)
- PIK3R2-related condition (5 variants)
- Overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes (5 variants)
- Seizure (3 variants)
- Endometrial Endometrioid Adenocarcinoma, Variant with Squamous Differentiation (1 variants)
- Overgrowth syndrome (1 variants)
- Intellectual disability (1 variants)
- Global developmental delay;Choreoathetosis;Aqueductal stenosis (1 variants)
- Megalencephaly-capillary malformation-polymicrogyria syndrome (1 variants)
Variants pathogenicity by type
Statistics on ClinVar variants can assist in determining whether a specific variant type in the PIK3R2 gene is commonly pathogenic or not.
In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.
Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.
| Variant type | Pathogenic | Likely pathogenic | VUS | Likely benign | Benign | Sum |
|---|---|---|---|---|---|---|
| synonymous | 72 | 12 | 88 | |||
| missense | 120 | 18 | 18 | 166 | ||
| nonsense | 2 | |||||
| start loss | 0 | |||||
| frameshift | 4 | |||||
| inframe indel | 3 | |||||
| splice donor/acceptor (+/-2bp) | 3 | |||||
| splice region ? | 3 | 13 | 4 | 20 | ||
| non coding ? | 35 | 23 | 60 | |||
| Total | 5 | 7 | 136 | 125 | 53 |
Highest pathogenic variant AF is 0.00000657
Variants in PIK3R2
This is a list of pathogenic ClinVar variants found in the PIK3R2 region.
You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.
| Position | Type | Phenotype | Significance | ClinVar |
|---|---|---|---|---|
| 19-18155196-C-CA | Benign (Sep 02, 2019) | |||
| 19-18155196-C-CAA | Benign (Aug 26, 2019) | |||
| 19-18155862-C-T | Likely benign (Apr 04, 2019) | |||
| 19-18155875-C-T | PIK3R2-related disorder | Likely benign (Oct 10, 2019) | ||
| 19-18155889-C-T | Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 1 • not specified | Benign (Jan 08, 2024) | ||
| 19-18155889-CCT-C | Uncertain significance (Aug 09, 2022) | |||
| 19-18155908-G-A | Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 1 | Uncertain significance (Sep 11, 2018) | ||
| 19-18155910-G-T | Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 1 | Uncertain significance (Jun 14, 2023) | ||
| 19-18155913-C-G | Inborn genetic diseases | Uncertain significance (May 17, 2023) | ||
| 19-18155915-G-A | Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 1 | Likely benign (May 15, 2023) | ||
| 19-18155921-G-A | Uncertain significance (Apr 01, 2016) | |||
| 19-18155921-G-C | Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 1 | Likely benign (Mar 01, 2023) | ||
| 19-18155925-C-G | Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 1 | Uncertain significance (Aug 05, 2023) | ||
| 19-18155925-C-T | Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 1 • Inborn genetic diseases | Conflicting classifications of pathogenicity (Jul 01, 2022) | ||
| 19-18155934-C-A | not specified | Likely benign (Aug 18, 2016) | ||
| 19-18155934-C-T | Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 1 | Likely benign (Mar 18, 2023) | ||
| 19-18155935-G-A | Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 1 | Uncertain significance (Jun 09, 2023) | ||
| 19-18155936-G-A | Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 1 | Likely benign (Dec 02, 2023) | ||
| 19-18155938-C-T | Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 1 | Uncertain significance (Oct 31, 2022) | ||
| 19-18155939-G-A | Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 1 • PIK3R2-related disorder | Likely benign (Jul 12, 2023) | ||
| 19-18155941-A-AGGACCTGGAGCTGCTGCCCGGCGAC | Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 1 | Uncertain significance (Jan 28, 2020) | ||
| 19-18155951-G-A | PIK3R2-related disorder | Likely benign (Sep 30, 2021) | ||
| 19-18155961-G-A | Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 1 • Inborn genetic diseases | Uncertain significance (May 01, 2022) | ||
| 19-18155966-C-T | Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 1 | Likely benign (Apr 20, 2022) | ||
| 19-18155982-C-T | Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 1 | Uncertain significance (Jul 26, 2023) |
GnomAD
Source:
| Gene | Type | Bio Type | Transcript | Coding Exons | Length |
|---|---|---|---|---|---|
| PIK3R2 | protein_coding | protein_coding | ENST00000222254 | 15 | 17423 |
| pLI Probability LOF Intolerant | pRec Probability LOF Recessive | Individuals with no LOFs | Individuals with Homozygous LOFs | Individuals with Heterozygous LOFs | Defined | p |
|---|---|---|---|---|---|---|
| 0.0163 | 0.984 | 125720 | 0 | 15 | 125735 | 0.0000597 |
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible in Transcript | |
|---|---|---|---|---|---|---|
| Missense | 2.33 | 295 | 431 | 0.684 | 0.0000299 | 4547 |
| Missense in Polyphen | 49 | 105.41 | 0.46487 | 1161 | ||
| Synonymous | 0.802 | 177 | 191 | 0.926 | 0.0000143 | 1482 |
| Loss of Function | 3.88 | 10 | 34.7 | 0.288 | 0.00000180 | 378 |
LoF frequencies by population
| Ethnicity | Sum of pLOFs | p |
|---|---|---|
| African & African-American | 0.000274 | 0.000272 |
| Ashkenazi Jewish | 0.0000995 | 0.0000992 |
| East Asian | 0.00 | 0.00 |
| Finnish | 0.0000462 | 0.0000462 |
| European (Non-Finnish) | 0.0000620 | 0.0000615 |
| Middle Eastern | 0.00 | 0.00 |
| South Asian | 0.00 | 0.00 |
| Other | 0.00 | 0.00 |
dbNSFP
Source:
- Function
- FUNCTION: Regulatory subunit of phosphoinositide-3-kinase (PI3K), a kinase 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. Binds to activated (phosphorylated) protein-tyrosine kinases, through its SH2 domain, and acts as an adapter, mediating the association of the p110 catalytic unit to the plasma membrane. Indirectly regulates autophagy (PubMed:23604317). Promotes nuclear translocation of XBP1 isoform 2 in a ER stress- and/or insulin- dependent manner during metabolic overloading in the liver and hence plays a role in glucose tolerance improvement (By similarity). {ECO:0000250|UniProtKB:O08908, ECO:0000269|PubMed:23604317}.;
- Disease
- DISEASE: Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 1 (MPPH1) [MIM:603387]: A syndrome characterized by megalencephaly, hydrocephalus, and polymicrogyria; polydactyly may also be seen. There is considerable phenotypic similarity between this disorder and the megalencephaly-capillary malformation syndrome. {ECO:0000269|PubMed:22729224, ECO:0000269|PubMed:23745724, ECO:0000269|PubMed:26520804, ECO:0000269|PubMed:26860062}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
- Pathway
- PI3K-Akt signaling pathway - Homo sapiens (human);Inflammatory mediator regulation of TRP channels - Homo sapiens (human);Non-small cell lung cancer - Homo sapiens (human);Platelet activation - Homo sapiens (human);Chronic myeloid leukemia - Homo sapiens (human);Gastric cancer - Homo sapiens (human);Focal adhesion - Homo sapiens (human);mTOR signaling pathway - Homo sapiens (human);Relaxin signaling pathway - Homo sapiens (human);Regulation of lipolysis in adipocytes - Homo sapiens (human);T cell receptor signaling pathway - Homo sapiens (human);B cell receptor signaling pathway - Homo sapiens (human);Fc epsilon RI signaling pathway - Homo sapiens (human);Fc gamma R-mediated phagocytosis - Homo sapiens (human);Kaposi,s sarcoma-associated herpesvirus infection - Homo sapiens (human);Renal cell carcinoma - Homo sapiens (human);VEGF signaling pathway - Homo sapiens (human);Neurotrophin signaling pathway - Homo sapiens (human);Central carbon metabolism in cancer - Homo sapiens (human);Choline metabolism in cancer - Homo sapiens (human);Melanoma - Homo sapiens (human);Type II diabetes mellitus - Homo sapiens (human);Insulin resistance - Homo sapiens (human);Non-alcoholic fatty liver disease (NAFLD) - Homo sapiens (human);AGE-RAGE signaling pathway in diabetic complications - Homo sapiens (human);HIF-1 signaling pathway - Homo sapiens (human);Jak-STAT signaling pathway - Homo sapiens (human);Longevity regulating pathway - multiple species - Homo sapiens (human);Small cell lung cancer - Homo sapiens (human);Influenza A - Homo sapiens (human);Acute myeloid leukemia - Homo sapiens (human);Breast cancer - Homo sapiens (human);ErbB signaling pathway - Homo sapiens (human);Autophagy - animal - Homo sapiens (human);Carbohydrate digestion and absorption - Homo sapiens (human);FoxO signaling pathway - Homo sapiens (human);TNF signaling pathway - Homo sapiens (human);Chemokine signaling pathway - Homo sapiens (human);HTLV-I infection - Homo sapiens (human);Amoebiasis - Homo sapiens (human);Regulation of actin cytoskeleton - Homo sapiens (human);Axon guidance - Homo sapiens (human);AMPK signaling pathway - Homo sapiens (human);Signaling pathways regulating pluripotency of stem cells - Homo sapiens (human);Hepatocellular carcinoma - Homo sapiens (human);Glioma - Homo sapiens (human);Thyroid hormone signaling pathway - Homo sapiens (human);Prostate cancer - Homo sapiens (human);Longevity regulating pathway - Homo sapiens (human);Chagas disease (American trypanosomiasis) - Homo sapiens (human);Toll-like receptor signaling pathway - Homo sapiens (human);cAMP signaling pathway - Homo sapiens (human);Estrogen signaling pathway - Homo sapiens (human);Fluid shear stress and atherosclerosis - Homo sapiens (human);C-type lectin receptor signaling pathway - Homo sapiens (human);Aldosterone-regulated sodium reabsorption - Homo sapiens (human);Rap1 signaling pathway - Homo sapiens (human);Ras signaling pathway - Homo sapiens (human);Natural killer cell mediated cytotoxicity - Homo sapiens (human);Sphingolipid signaling pathway - Homo sapiens (human);Phosphatidylinositol signaling system - Homo sapiens (human);Phospholipase D signaling pathway - Homo sapiens (human);Bacterial invasion of epithelial cells - Homo sapiens (human);Proteoglycans in cancer - Homo sapiens (human);Prolactin signaling pathway - Homo sapiens (human);MicroRNAs in cancer - Homo sapiens (human);Pathways in cancer - Homo sapiens (human);Viral carcinogenesis - Homo sapiens (human);Hepatitis C - Homo sapiens (human);Hepatitis B - Homo sapiens (human);Measles - Homo sapiens (human);Osteoclast differentiation - Homo sapiens (human);Apoptosis - Homo sapiens (human);Cellular senescence - Homo sapiens (human);Cholinergic synapse - Homo sapiens (human);Epstein-Barr virus infection - Homo sapiens (human);Pancreatic cancer - Homo sapiens (human);Endometrial cancer - Homo sapiens (human);Colorectal cancer - Homo sapiens (human);Insulin signaling pathway - Homo sapiens (human);EGFR Inhibitor Pathway, Pharmacodynamics;Human papillomavirus infection - Homo sapiens (human);Leukocyte transendothelial migration - Homo sapiens (human);Progesterone-mediated oocyte maturation - Homo sapiens (human);Anti-diabetic Drug Potassium Channel Inhibitors Pathway, Pharmacodynamics;Sorafenib Pharmacodynamics;IL-5 Signaling Pathway;Androgen receptor signaling pathway;AMP-activated Protein Kinase (AMPK) Signaling;Regulation of toll-like receptor signaling pathway;MicroRNAs in cardiomyocyte hypertrophy;IL-1 signaling pathway;RANKL-RANK (Receptor activator of NFKB (ligand)) Signaling Pathway;Integrin-mediated Cell Adhesion;Leptin signaling pathway;Human Thyroid Stimulating Hormone (TSH) signaling pathway;Prolactin Signaling Pathway;IL-7 Signaling Pathway;IL-9 Signaling Pathway;Signaling Pathways in Glioblastoma;B Cell Receptor Signaling Pathway;Interleukin-11 Signaling Pathway;Brain-Derived Neurotrophic Factor (BDNF) signaling pathway;Alpha 6 Beta 4 signaling pathway;JAK-STAT;Bladder Cancer;IL-3 Signaling Pathway;Kit receptor signaling pathway;Focal Adhesion;IL-6 signaling pathway;TGF-beta Signaling Pathway;PI3K-AKT-mTOR signaling pathway and therapeutic opportunities;IL-4 Signaling Pathway;VEGFA-VEGFR2 Signaling Pathway;Angiopoietin Like Protein 8 Regulatory Pathway;Chemokine signaling pathway;ESC Pluripotency Pathways;Focal Adhesion-PI3K-Akt-mTOR-signaling pathway;Microglia Pathogen Phagocytosis Pathway;Endometrial cancer;PI3K-Akt Signaling Pathway;MET in type 1 papillary renal cell carcinoma;Ras Signaling;EMT transition in Colorectal Cancer;EGF-EGFR Signaling Pathway;Insulin Signaling;Regulation of Actin Cytoskeleton;G13 Signaling Pathway;Interferon type I signaling pathways;Notch Signaling Pathway;T-Cell antigen Receptor (TCR) Signaling Pathway;DNA Damage Response (only ATM dependent);Toll-like Receptor Signaling Pathway;Signaling by GPCR;Interleukin-7 signaling;Disease;Signal Transduction;Signaling by Interleukins;DAP12 signaling;DAP12 interactions;VEGFA-VEGFR2 Pathway;Metabolism of lipids;Cytokine Signaling in Immune system;Alpha6Beta4Integrin;B cell receptor signaling;Downstream TCR signaling;TCR signaling;CD28 dependent PI3K/Akt signaling;CD28 co-stimulation;PI3K Cascade;Costimulation by the CD28 family;IRS-mediated signalling;Insulin receptor signalling cascade;Signaling by Insulin receptor;Signaling by PDGF;Role of phospholipids in phagocytosis;Fcgamma receptor (FCGR) dependent phagocytosis;Fc epsilon receptor (FCERI) signaling;TCR;IGF signaling;Innate Immune System;Immune System;Metabolism;3-phosphoinositide biosynthesis;Interleukin receptor SHC signaling;Interleukin-2 family signaling;Adaptive Immune System;superpathway of inositol phosphate compounds;KitReceptor;insulin Mam;Rho GTPase cycle;BCR;AndrogenReceptor;GPVI-mediated activation cascade;IL1;Platelet activation, signaling and aggregation;IL-7 signaling;Signaling by Rho GTPases;Signaling by NTRK1 (TRKA);TGF_beta_Receptor;Signaling by NTRKs;EGFR1;Tie2 Signaling;Cell surface interactions at the vascular wall;Hemostasis;PI3K/AKT activation;PIP3 activates AKT signaling;PDGF;IL2;IL11;EPO signaling;IL3;Gastrin;Downstream signal transduction;Synthesis of PIPs at the plasma membrane;PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling;Negative regulation of the PI3K/AKT network;Signaling by VEGF;PI Metabolism;IL4;Phospholipid metabolism;G alpha (12/13) signalling events;Signaling by SCF-KIT;Leptin;Constitutive Signaling by Aberrant PI3K in Cancer;PI3K/AKT Signaling in Cancer;IL6;IRS-related events triggered by IGF1R;IGF1R signaling cascade;Signaling by Receptor Tyrosine Kinases;Nephrin family interactions;Cell-Cell communication;G alpha (q) signalling events;G beta:gamma signalling through PI3Kgamma;G-protein beta:gamma signalling;GPCR downstream signalling;Intracellular signaling by second messengers;Diseases of signal transduction;Signaling by Type 1 Insulin-like Growth Factor 1 Receptor (IGF1R);CD4 T cell receptor signaling-NFkB cascade;Role of LAT2/NTAL/LAB on calcium mobilization;insulin;CD4 T cell receptor signaling;Regulation of signaling by CBL;Interleukin-3, 5 and GM-CSF signaling
(Consensus)
Recessive Scores
- pRec
- 0.418
Intolerance Scores
- loftool
- rvis_EVS
- -0.53
- rvis_percentile_EVS
- 20.7
Haploinsufficiency Scores
- pHI
- 0.470
- hipred
- Y
- hipred_score
- 0.743
- ghis
- 0.590
Essentials
- essential_gene_CRISPR
- N
- essential_gene_CRISPR2
- S
- essential_gene_gene_trap
- N
- gene_indispensability_pred
- E
- gene_indispensability_score
- 0.983
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |
Mouse Genome Informatics
- Gene name
- Pik3r2
- Phenotype
- neoplasm; cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); homeostasis/metabolism phenotype; muscle phenotype; growth/size/body region phenotype;
Gene ontology
- Biological process
- cellular glucose homeostasis;insulin receptor signaling pathway;regulation of autophagy;phosphatidylinositol 3-kinase signaling;protein transport;cellular response to insulin stimulus;response to endoplasmic reticulum stress;phosphatidylinositol-3-phosphate biosynthetic process;Fc-epsilon receptor signaling pathway;Fc-gamma receptor signaling pathway involved in phagocytosis;positive regulation of protein import into nucleus;negative regulation of MAPK cascade;positive regulation of GTPase activity;regulation of phosphatidylinositol 3-kinase activity;positive regulation of transcription by RNA polymerase II;phosphatidylinositol phosphorylation;vascular endothelial growth factor receptor signaling pathway;phosphatidylinositol-mediated signaling;T cell receptor signaling pathway;leukocyte migration;regulation of small GTPase mediated signal transduction;positive regulation of protein kinase B signaling
- Cellular component
- nucleus;cytosol;phosphatidylinositol 3-kinase complex
- Molecular function
- phosphotyrosine residue binding;GTPase activator activity;protein binding;1-phosphatidylinositol-3-kinase activity;protein phosphatase binding;receptor tyrosine kinase binding;phosphatidylinositol-4,5-bisphosphate 3-kinase activity;1-phosphatidylinositol-3-kinase regulator activity;protein heterodimerization activity