PIK3CD

phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta, the group of Phosphatidylinositol 3-kinase subunits

Basic information

Region (hg38): 1:9629888-9729114

Links

ENSG00000171608 ∙ NCBI:5293 ∙ OMIM:602839 ∙ HGNC:8977 ∙ Uniprot:O00329 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• activated PI3K-delta syndrome (Supportive), mode of inheritance: AD
• immunodeficiency 14 (Strong), mode of inheritance: AD
• immunodeficiency 14b, autosomal recessive (Limited), mode of inheritance: Unknown
• immunodeficiency 14b, autosomal recessive (Definitive), mode of inheritance: AR
• immunodeficiency 14 (Definitive), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Immunodeficiency 14A with lymphoproliferation, autosomal dominant; Immunodeficiency 14B, autosomal recessive	AD/AR	Allergy/Immunology/Infectious; Oncologic	Individuals with Immunodeficiency 14A and Immunodeficiency 14B have been described as having a primary immunodeficiency, with susceptibility to respiratory and other infections, and antiinfectious prophylaxis and early and aggressive treatment of infections may be beneficial; In Immunodeficiency 14A with lymphoproliferation, autosomal dominant, medical management (with leniolisib, a small molecule inhibitor) has been shown to be beneficial related to immunoproliferation and via immunophenotyping; Individuals with Immunodeficiency 14A, autosomal dominant have been described as developing lymphoma, and awareness may allow early recognition and management	Allergy/Immunology/Infectious; Oncologic	24136356; 24165795; 24610295; 28972011; 30040974; 30018075; 30336224; 36399712
Biallelic variants, along with biallelic variants in KNSTRN, have been described as causing Roifman-Chitayat syndrome, digenic

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the PIK3CD gene.

• Immunodeficiency 14 (646 variants)
• not provided (95 variants)
• not specified (31 variants)
• Inborn genetic diseases (14 variants)
• PIK3CD-related condition (11 variants)
• Immunodeficiency 14;Combined immunodeficiency with faciooculoskeletal anomalies;Immunodeficiency 14b, autosomal recessive (4 variants)
• Immunodeficiency 14b, autosomal recessive (4 variants)
• Combined immunodeficiency with faciooculoskeletal anomalies;Immunodeficiency 14;Immunodeficiency 14b, autosomal recessive (3 variants)
• See cases (2 variants)
• Combined immunodeficiency with faciooculoskeletal anomalies (2 variants)
• Immunodeficiency 14b, autosomal recessive;Immunodeficiency 14;Combined immunodeficiency with faciooculoskeletal anomalies (1 variants)
• Inherited Immunodeficiency Diseases (1 variants)
• Abnormality of the immune system (1 variants)
• Combined immunodeficiency with faciooculoskeletal anomalies;Immunodeficiency 14b, autosomal recessive;Immunodeficiency 14 (1 variants)
• Activated PI3K-delta syndrome (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the PIK3CD 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			6	204	19	229
missense	5	3	240	9	3	260
nonsense	1		3			4
start loss						0
frameshift		1	3			4
inframe indel			2			2
splice donor/acceptor (+/-2bp)			3			3
splice region			17	25	8	50
non coding			6	106	29	141
Total	6	4	263	319	51

Variants in PIK3CD

This is a list of pathogenic ClinVar variants found in the PIK3CD region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
1-9654282-C-T			Likely benign (Dec 01, 2022)
1-9654307-G-A			Likely benign (Jun 01, 2023)
1-9654484-G-C		not specified	Benign (-)
1-9710459-C-A		Immunodeficiency 14	Likely benign (Jan 10, 2024)
1-9710460-C-T		Immunodeficiency 14	Uncertain significance (Jun 29, 2023)
1-9710461-C-T		Immunodeficiency 14	Likely benign (Sep 11, 2018)
1-9710463-C-T		Immunodeficiency 14	Uncertain significance (Oct 24, 2022)
1-9710467-G-A		Immunodeficiency 14	Likely benign (Dec 22, 2021)
1-9710467-G-T		Immunodeficiency 14	Likely benign (Jun 14, 2023)
1-9710472-A-C		Immunodeficiency 14	Uncertain significance (Nov 07, 2023)
1-9710472-A-G		Immunodeficiency 14	Uncertain significance (Nov 27, 2023)
1-9710479-C-A		Immunodeficiency 14	Likely benign (Oct 19, 2020)
1-9710485-A-C		Immunodeficiency 14 • PIK3CD-related disorder	Uncertain significance (Oct 04, 2023)
1-9710494-C-G		Immunodeficiency 14	Likely benign (Apr 02, 2022)
1-9710496-A-C		Immunodeficiency 14	Uncertain significance (Oct 08, 2019)
1-9710512-C-T		Immunodeficiency 14	Likely benign (Nov 13, 2023)
1-9710513-G-A		Immunodeficiency 14	Uncertain significance (Nov 06, 2023)
1-9710517-T-C		Immunodeficiency 14	Uncertain significance (Jul 18, 2023)
1-9710524-C-T		Immunodeficiency 14	Likely benign (Aug 15, 2022)
1-9710530-G-C		Immunodeficiency 14	Likely benign (Aug 07, 2023)
1-9710531-C-T		Immunodeficiency 14	Likely benign (Nov 01, 2022)
1-9710539-A-G		Immunodeficiency 14	Likely benign (Nov 11, 2019)
1-9710542-G-C		Immunodeficiency 14	Likely benign (Aug 29, 2022)
1-9710554-C-T		Immunodeficiency 14	Likely benign (Oct 22, 2023)
1-9710558-CCT-C		Immunodeficiency 14	Uncertain significance (Mar 24, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
PIK3CD	protein_coding	protein_coding	ENST00000377346	22	77383

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.00	0.0000133	125732	0	16	125748	0.0000636

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	4.27	331	634	0.522	0.0000459	6842
Missense in Polyphen		76	247.34	0.30727		2855
Synonymous	-1.16	308	283	1.09	0.0000216	2058
Loss of Function	6.15	5	53.6	0.0933	0.00000281	583

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000120	0.000119
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.00	0.00
European (Non-Finnish)	0.000116	0.000105
Middle Eastern	0.00	0.00
South Asian	0.0000328	0.0000327
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Phosphoinositide-3-kinase (PI3K) that phosphorylates PftdIns(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. Mediates immune responses. Plays a role in B-cell development, proliferation, migration, and function. Required for B-cell receptor (BCR) signaling. Mediates B-cell proliferation response to anti-IgM, anti-CD40 and IL4 stimulation. Promotes cytokine production in response to TLR4 and TLR9. Required for antibody class switch mediated by TLR9. Involved in the antigen presentation function of B-cells. Involved in B-cell chemotaxis in response to CXCL13 and sphingosine 1-phosphate (S1P). Required for proliferation, signaling and cytokine production of naive, effector and memory T-cells. Required for T-cell receptor (TCR) signaling. Mediates TCR signaling events at the immune synapse. Activation by TCR leads to antigen-dependent memory T-cell migration and retention to antigenic tissues. Together with PIK3CG participates in T-cell development. Contributes to T-helper cell expansion and differentiation. Required for T-cell migration mediated by homing receptors SELL/CD62L, CCR7 and S1PR1 and antigen dependent recruitment of T-cells. Together with PIK3CG is involved in natural killer (NK) cell development and migration towards the sites of inflammation. Participates in NK cell receptor activation. Have a role in NK cell maturation and cytokine production. Together with PIK3CG is involved in neutrophil chemotaxis and extravasation. Together with PIK3CG participates in neutrophil respiratory burst. Have important roles in mast-cell development and mast cell mediated allergic response. Involved in stem cell factor (SCF)-mediated proliferation, adhesion and migration. Required for allergen-IgE-induced degranulation and cytokine release. The lipid kinase activity is required for its biological function. Isoform 2 may be involved in stabilizing total RAS levels, resulting in increased ERK phosphorylation and increased PI3K activity. {ECO:0000269|PubMed:20081091, ECO:0000269|PubMed:22020336}.
• Disease: DISEASE: Activated PI3K-delta syndrome (APDS) [MIM:615513]: A disorder characterized by recurrent respiratory infections, progressive airway damage, lymphopenia, increased circulating transitional B cells, increased immunoglobulin M, reduced immunoglobulin G2 levels in serum, and impaired vaccine responses. {ECO:0000269|PubMed:24136356}. 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);Inositol phosphate metabolism - 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);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;Phosphatidylinositol Phosphate Metabolism;Joubert syndrome;AMP-activated Protein Kinase (AMPK) Signaling;Regulation of toll-like receptor signaling pathway;MicroRNAs in cardiomyocyte hypertrophy;Angiogenesis overview;Signaling Pathways in Glioblastoma;IL-3 Signaling Pathway;Focal Adhesion;Overview of nanoparticle effects;IL-4 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;Insulin Signaling;Regulation of Actin Cytoskeleton;G13 Signaling Pathway;Interferon type I signaling pathways;DNA Damage Response (only ATM dependent);Toll-like Receptor Signaling Pathway;Signaling by GPCR;Antigen activates B Cell Receptor (BCR) leading to generation of second messengers;Disease;Signal Transduction;Signaling by Interleukins;Metabolism of lipids;Cytokine Signaling in Immune system;Alpha6Beta4Integrin;B cell receptor signaling;Signaling by the B Cell Receptor (BCR);Inositol phosphate metabolism;HGF;IGF signaling;Immune System;Metabolism;3-phosphoinositide biosynthesis;FGF;Interleukin receptor SHC signaling;Interleukin-2 family signaling;Adaptive Immune System;superpathway of inositol phosphate compounds;insulin Mam;IL-7 signaling;Phosphatidylinositol phosphate metabolism;EGFR1;PIP3 activates AKT signaling;PDGF;IL2;EPO signaling;IL3;Synthesis of PIPs at the plasma membrane;PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling;Negative regulation of the PI3K/AKT network;PI Metabolism;IL4;Phospholipid metabolism;Constitutive Signaling by Aberrant PI3K in Cancer;PI3K/AKT Signaling in Cancer;VEGF;G beta:gamma signalling through PI3Kgamma;G-protein beta:gamma signalling;GPCR downstream signalling;Intracellular signaling by second messengers;Diseases of signal transduction;CD4 T cell receptor signaling-NFkB cascade;insulin;CD4 T cell receptor signaling;Regulation of signaling by CBL;Interleukin-3, 5 and GM-CSF signaling (Consensus)

Recessive Scores

• pRec: 0.314

Intolerance Scores

• loftool: 0.183
• rvis_EVS: -1.66
• rvis_percentile_EVS: 2.72

Haploinsufficiency Scores

• pHI: 0.614
• hipred: Y
• hipred_score: 0.851
• ghis: 0.653

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: H
• gene_indispensability_pred: E
• gene_indispensability_score: 0.995

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium

Mouse Genome Informatics

• Gene name: Pik3cd
• Phenotype: hematopoietic system phenotype; immune system phenotype; skeleton phenotype; digestive/alimentary phenotype; endocrine/exocrine gland phenotype; cellular phenotype; homeostasis/metabolism phenotype

Zebrafish Information Network

• Gene name: pik3cd
• Affected structure: retinal ganglion cell
• Phenotype tag: abnormal
• Phenotype quality: decreased branchiness

Gene ontology

• Biological process: natural killer cell differentiation;cytokine production;adaptive immune response;mast cell chemotaxis;respiratory burst involved in defense response;protein phosphorylation;inflammatory response;signal transduction;axon guidance;positive regulation of gene expression;negative regulation of gene expression;T cell chemotaxis;phosphatidylinositol 3-kinase signaling;positive regulation of phosphatidylinositol 3-kinase signaling;phosphorylation;cell migration;cytokine-mediated signaling pathway;natural killer cell activation;platelet activation;T cell differentiation;positive regulation of cell migration;neutrophil chemotaxis;positive regulation of neutrophil apoptotic process;natural killer cell chemotaxis;B cell chemotaxis;phosphatidylinositol-3-phosphate biosynthetic process;T cell activation;B cell activation;mast cell degranulation;innate immune response;phosphatidylinositol phosphorylation;phosphatidylinositol-mediated signaling;T cell receptor signaling pathway;B cell receptor signaling pathway;positive regulation of protein kinase B signaling;mast cell differentiation;neutrophil extravasation
• Cellular component: cytoplasm;cytosol;plasma membrane;phosphatidylinositol 3-kinase complex;membrane;mast cell granule
• Molecular function: protein binding;ATP binding;kinase activity;1-phosphatidylinositol-3-kinase activity;phosphatidylinositol 3-kinase activity;1-phosphatidylinositol-4-phosphate 3-kinase activity;phosphatidylinositol-4,5-bisphosphate 3-kinase activity