GeneBe

PIK3R2

protein-coding

phosphoinositide-3-kinase regulatory subunit 2, the group of SH2 domain containing

Gene summary

Phosphatidylinositol 3-kinase (PI3K) is a lipid kinase that phosphorylates phosphatidylinositol and similar compounds, creating second messengers important in growth signaling pathways. PI3K functions as a heterodimer of a regulatory and a catalytic subunit. The protein encoded by this gene is a regulatory component of PI3K. Three transcript variants, one protein coding and the other two non-protein coding, have been found for this gene. [provided by RefSeq, Apr 2019]

MANE transcript

NM_005027.4

Inheritance

AD

ClinVar variants

P:18U:247B:209

Top phenotype

Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 1

gnomAD constraint

pLI —, LoF o/e 0.29

Max pathogenic AF

—

Genomic locus

chr19:18,153,163-18,170,540

External References & Databases

Ensembl (ENSG00000105647)NCBI Gene (5296)OMIM (603157)HGNC:8980GenCCUniProt (O00459)AlphaFoldClinVar (PIK3R2)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~17.4 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genesDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0100283

Submitter: ClinGen

PIK3R2 was first reported in relation to autosomal dominant overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes in 2012 (Riviere et al., PMID: 22729224). At least 4 unique de novo missense variants have been reported in humans. Evidence supporting this gene-disease relationship including case-level data, case-control data, and experimental data. Variants in this gene have been reported in at least 35 probands in at least 4 publications (PMIDs: 22729224, 26520804, 26860062, 23745724) with the vast majority of cases accounted for by recurrent a c.1117G>A (p.G373R) mutation (PMID: 26520804). More evidence is available in the literature, but the maximal score for genetic evidence (12 pts) has been reached. The mechanism of disease is heterozygous gain of function (PMID: 28086757). This gene-disease relationship is supported by cell culture assays using patient derived cells. In summary, PIK3R2 is definitively associated with autosomal dominant overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes. This association has been repeatedly demonstrated in both the research and clinical diagnostic settings, and it has been upheld over time. This classification was approved by the ClinGen Brain Malformations Gene Curation Expert Panel on 3/23/2021 (SOP Version 7).

megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 1DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0011313

Submitter: G2P

megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 1STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0011313

Submitter: Labcorp Genetics (formerly Invitae)

megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 1DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0011313

Submitter: Illumina

megalencephaly-polymicrogyria-postaxial polydactyly-hydrocephalus syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0019375

Submitter: Orphanet

megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 1STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0011313

Submitter: Genomics England PanelApp

megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 1STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0011313

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 1AD

Manifestation: Craniofacial; Musculoskeletal; Neurologic

Intervention: General

Rationale: 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

Refs: 17675034; 22729224; 23745724Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PIK3R2 variants in ClinVar

13 Conditions Cataloged
Megalencephaly-polymicrogyria-postaxial polydactyly-hydrocephalus syndromeTotal: 331
not providedTotal: 176
Inborn genetic diseasesTotal: 105
not specifiedTotal: 75
PIK3R2-related disorderTotal: 51
Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 1Total: 38
Overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genesTotal: 5
SeizureTotal: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_005027.4. 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.

EffectPLPVUSLBBSum
synonymous
7
clinvar
140
clinvar
6
clinvar
 153
missense
5
clinvar
9
clinvar
219
clinvar
47
clinvar
15
clinvar
 295
nonsense
2
clinvar
4
clinvar
1
clinvar
 7
start loss
0
frameshift
8
clinvar
 8
splice donor/acceptor (+/-2bp)
1
clinvar
1
clinvar
9
clinvar
 11
Total61224718821474

Highest pathogenic variant AF is 0.000006573585

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 46 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_005027.4RefSeqNP_005018.215MANE Select
ENST00000222254.13EnsemblENSP00000222254.615MANE Select
ENST00000426902.5EnsemblENSP00000395636.111Standard
ENST00000464016.3EnsemblENSP00000476825.14Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • 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)

Biological Process

  • cellular glucose homeostasis
  • insulin receptor signaling pathway
  • regulation of autophagy
  • phosphatidylinositol 3-kinase signaling
  • protein transport

Molecular Function

  • phosphotyrosine residue binding
  • GTPase activator activity
  • protein binding
  • 1-phosphatidylinositol-3-kinase activity
  • protein phosphatase binding

Cellular Component

  • nucleus
  • cytosol
  • phosphatidylinositol 3-kinase complex

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000222254
Coding exons
15
Length
17423
Individuals with no LoFs
125720
Homozygous LoFs
0
Heterozygous LoFs
15
Defined
125735
p
0.0000597
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense2.332954310.6840.00002994547
Missense (PolyPhen)49105.410.464871161
Synonymous0.8021771910.9260.00001431482
Loss of Function3.881034.70.2880.00000180378

Population LoF Frequency

PopulationCAFp-valueStatus
African0.000190.00018rare
Latino/Admixed American0.0000870.000087rare
Ashkenazi Jewish0.0000990.000099rare
East Asian00.0absent
Finnish0.0000460.000046rare
European (Non-Finnish)0.0000620.000062rare
South Asian00.0absent
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

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.;

Recessive Scores

pRec
0.418

Intolerance Scores

RVIS EVS
-0.53
RVIS percentile EVS
20.7

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
S
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.983

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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