IKBKB

inhibitor of nuclear factor kappa B kinase subunit beta, the group of I kappa B kinases|IKK complex

Basic information

Region (hg38): 8:42271301-42332460

Links

ENSG00000104365 ∙ NCBI:3551 ∙ OMIM:603258 ∙ HGNC:5960 ∙ Uniprot:O14920 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• immunodeficiency 15a (Moderate), mode of inheritance: AD
• severe combined immunodeficiency due to IKK2 deficiency (Strong), mode of inheritance: AR
• severe combined immunodeficiency due to IKK2 deficiency (Supportive), mode of inheritance: AR
• severe combined immunodeficiency due to IKK2 deficiency (Strong), mode of inheritance: AR
• immunodeficiency 15a (Strong), mode of inheritance: AD
• severe combined immunodeficiency due to IKK2 deficiency (Definitive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Immunodeficiency 15A; Immunodeficiency 15B	AD/AR	Allergy/Immunology/Infectious	Individuals may be susceptible to severe and recurrent infections, and prophylaxis and early and aggressive treatment of infections may be beneficial; BMT/HSCT has been described in Immunodeficiency 15B	Allergy/Immunology/Infectious	24369075; 25216719

ClinVar

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

• Severe combined immunodeficiency due to IKK2 deficiency (407 variants)
• not provided (33 variants)
• Inborn genetic diseases (15 variants)
• not specified (12 variants)
• Immunodeficiency 15a (6 variants)
• IKBKB-related condition (6 variants)
• Severe combined immunodeficiency disease (2 variants)
• Severe combined immunodeficiency due to IKK2 deficiency;Immunodeficiency 15a (1 variants)
• See cases (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the IKBKB 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			4	103	5	112
missense	1		150	11	7	169
nonsense	6	1	2			9
start loss						0
frameshift	5	1	1			7
inframe indel			3			3
splice donor/acceptor (+/-2bp)		4				4
splice region			10	24	2	36
non coding			2	75	25	102
Total	12	6	162	189	37

Highest pathogenic variant AF is 0.0000132

Variants in IKBKB

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

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

Position	Type	Phenotype	Significance	ClinVar
8-42271381-G-C		IKBKB-related disorder	Likely benign (Nov 30, 2023)
8-42271382-G-A			Likely benign (Mar 01, 2023)
8-42271424-C-T		not specified	Benign (Jan 24, 2024)
8-42271430-C-G		IKBKB-related disorder	Likely benign (May 07, 2020)
8-42271448-T-A		IKBKB-related disorder	Likely benign (Jan 16, 2024)
8-42271448-T-C		IKBKB-related disorder	Benign (Oct 31, 2019)
8-42271464-C-G		IKBKB-related disorder	Uncertain significance (Oct 20, 2023)
8-42271477-C-T		IKBKB-related disorder	Benign (Sep 23, 2019)
8-42271987-A-T		not specified	Benign (Jan 24, 2024)
8-42272079-A-G			Likely benign (-)
8-42272108-G-T		Inborn genetic diseases	Uncertain significance (Nov 03, 2022)
8-42272111-C-A		IKBKB-related disorder	Likely pathogenic (May 01, 2023)
8-42272113-C-A		Severe combined immunodeficiency due to IKK2 deficiency	Uncertain significance (Oct 30, 2023)
8-42272114-C-T		Severe combined immunodeficiency due to IKK2 deficiency	Uncertain significance (Aug 09, 2022)
8-42272123-CA-C		Severe combined immunodeficiency due to IKK2 deficiency	Pathogenic (May 05, 2021)
8-42272127-G-A		Severe combined immunodeficiency due to IKK2 deficiency	Likely benign (Jan 24, 2023)
8-42272132-C-T		Severe combined immunodeficiency due to IKK2 deficiency	Uncertain significance (Sep 24, 2021)
8-42272138-G-A		Severe combined immunodeficiency due to IKK2 deficiency	Uncertain significance (Apr 12, 2022)
8-42272142-C-T		Severe combined immunodeficiency due to IKK2 deficiency	Likely benign (Jun 15, 2023)
8-42272172-G-C		Severe combined immunodeficiency due to IKK2 deficiency	Likely benign (Jul 06, 2023)
8-42272181-A-T		Severe combined immunodeficiency due to IKK2 deficiency	Likely benign (Dec 22, 2023)
8-42272190-C-G		Severe combined immunodeficiency due to IKK2 deficiency	Uncertain significance (Jun 14, 2020)
8-42272193-A-G		Severe combined immunodeficiency due to IKK2 deficiency	Likely benign (Feb 16, 2023)
8-42272213-C-T		Severe combined immunodeficiency due to IKK2 deficiency	Likely benign (Dec 26, 2023)
8-42272215-C-T		Severe combined immunodeficiency due to IKK2 deficiency	Likely benign (Apr 17, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
IKBKB	protein_coding	protein_coding	ENST00000520810	21	61154

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.992	0.00808	125736	0	12	125748	0.0000477

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	2.59	285	437	0.652	0.0000251	4968
Missense in Polyphen		66	148.66	0.44398		1658
Synonymous	2.04	140	174	0.803	0.0000104	1409
Loss of Function	5.68	9	54.1	0.166	0.00000319	532

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.0000289	0.0000289
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.000185	0.000185
European (Non-Finnish)	0.0000545	0.0000527
Middle Eastern	0.00	0.00
South Asian	0.0000375	0.0000327
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Serine kinase that plays an essential role in the NF- kappa-B signaling pathway which is activated by multiple stimuli such as inflammatory cytokines, bacterial or viral products, DNA damages or other cellular stresses. Acts as part of the canonical IKK complex in the conventional pathway of NF-kappa-B activation and phosphorylates inhibitors of NF-kappa-B on 2 critical serine residues. These modifications allow polyubiquitination of the inhibitors and subsequent degradation by the proteasome. In turn, free NF-kappa-B is translocated into the nucleus and activates the transcription of hundreds of genes involved in immune response, growth control, or protection against apoptosis. In addition to the NF-kappa-B inhibitors, phosphorylates several other components of the signaling pathway including NEMO/IKBKG, NF-kappa-B subunits RELA and NFKB1, as well as IKK-related kinases TBK1 and IKBKE. IKK-related kinase phosphorylations may prevent the overproduction of inflammatory mediators since they exert a negative regulation on canonical IKKs. Phosphorylates FOXO3, mediating the TNF- dependent inactivation of this pro-apoptotic transcription factor. Also phosphorylates other substrates including NCOA3, BCL10 and IRS1. Within the nucleus, acts as an adapter protein for NFKBIA degradation in UV-induced NF-kappa-B activation. {ECO:0000269|PubMed:11297557, ECO:0000269|PubMed:15084260, ECO:0000269|PubMed:17213322, ECO:0000269|PubMed:19716809, ECO:0000269|PubMed:20410276, ECO:0000269|PubMed:20434986, ECO:0000269|PubMed:20797629, ECO:0000269|PubMed:21138416}.
• Disease: DISEASE: Immunodeficiency 15 (IMD15) [MIM:615592]: An autosomal recessive primary immunodeficiency disorder characterized by onset in infancy of life-threatening bacterial, fungal, and viral infections and failure to thrive. Laboratory studies show hypo- or agammaglobulinemia with relatively normal numbers of B and T- cells, and impaired differentiation and activation of immune cells. {ECO:0000269|PubMed:24369075}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: PI3K-Akt signaling pathway - Homo sapiens (human);Chronic myeloid leukemia - Homo sapiens (human);mTOR signaling pathway - Homo sapiens (human);Adipocytokine signaling pathway - Homo sapiens (human);T cell receptor signaling pathway - Homo sapiens (human);B cell receptor signaling pathway - Homo sapiens (human);Kaposi,s sarcoma-associated herpesvirus infection - Homo sapiens (human);Neurotrophin signaling pathway - Homo sapiens (human);Type II diabetes mellitus - Homo sapiens (human);Insulin resistance - Homo sapiens (human);Non-alcoholic fatty liver disease (NAFLD) - Homo sapiens (human);Small cell lung cancer - Homo sapiens (human);Influenza A - Homo sapiens (human);Acute myeloid leukemia - 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);Cytosolic DNA-sensing pathway - Homo sapiens (human);Epithelial cell signaling in Helicobacter pylori infection - Homo sapiens (human);Prostate cancer - Homo sapiens (human);Chagas disease (American trypanosomiasis) - Homo sapiens (human);Toll-like receptor signaling pathway - Homo sapiens (human);NOD-like receptor signaling pathway - Homo sapiens (human);Fluid shear stress and atherosclerosis - Homo sapiens (human);C-type lectin receptor signaling pathway - Homo sapiens (human);Th17 cell differentiation - Homo sapiens (human);Th1 and Th2 cell differentiation - Homo sapiens (human);Ras signaling pathway - Homo sapiens (human);MAPK signaling pathway - Homo sapiens (human);IL-17 signaling pathway - Homo sapiens (human);Toxoplasmosis - Homo sapiens (human);Shigellosis - Homo sapiens (human);MicroRNAs in cancer - Homo sapiens (human);Pathways in cancer - Homo sapiens (human);Hepatitis C - Homo sapiens (human);Hepatitis B - Homo sapiens (human);Osteoclast differentiation - Homo sapiens (human);Apoptosis - Homo sapiens (human);NF-kappa B signaling pathway - Homo sapiens (human);Epstein-Barr virus infection - Homo sapiens (human);Pancreatic cancer - Homo sapiens (human);RIG-I-like receptor signaling pathway - Homo sapiens (human);Insulin signaling pathway - Homo sapiens (human);Human papillomavirus infection - Homo sapiens (human);Herpes simplex infection - Homo sapiens (human);Intracellular Signalling Through Adenosine Receptor A2b and Adenosine;Intracellular Signalling Through Adenosine Receptor A2a and Adenosine;Nucleotide-binding Oligomerization Domain (NOD) pathway;Osteopontin Signaling;Regulation of toll-like receptor signaling pathway;MicroRNAs in cardiomyocyte hypertrophy;Type II diabetes mellitus;Apoptosis Modulation and Signaling;IL-1 signaling pathway;RANKL-RANK (Receptor activator of NFKB (ligand)) Signaling Pathway;Leptin signaling pathway;TNF related weak inducer of apoptosis (TWEAK) Signaling Pathway;IL17 signaling pathway;B Cell Receptor Signaling Pathway;TNF alpha Signaling Pathway;AGE-RAGE pathway;Interleukin-11 Signaling Pathway;Brain-Derived Neurotrophic Factor (BDNF) signaling pathway;Quercetin and Nf-kB- AP-1 Induced Cell Apoptosis;Apoptosis;Polycystic Kidney Disease Pathway;JAK-STAT;EBV LMP1 signaling;Structural Pathway of Interleukin 1 (IL-1);Cardiac Hypertrophic Response;Hair Follicle Development- Induction (Part 1 of 3);NLR Proteins;Rac1-Pak1-p38-MMP-2 pathway;Photodynamic therapy-induced NF-kB survival signaling;Apoptotic Signaling Pathway;MAPK Signaling Pathway;MAPK and NFkB Signalling Pathways Inhibited by Yersinia YopJ;Toll-like Receptor Signaling;T-Cell antigen Receptor (TCR) pathway during Staphylococcus aureus infection;RIG-I-like Receptor Signaling;IL-4 Signaling Pathway;Chemokine signaling pathway;Focal Adhesion-PI3K-Akt-mTOR-signaling pathway;Fibrin Complement Receptor 3 Signaling Pathway;PI3K-Akt Signaling Pathway;Ras Signaling;Insulin Signaling;T-Cell antigen Receptor (TCR) Signaling Pathway;Estrogen signaling pathway;Toll-like Receptor Signaling Pathway;RAGE;TLR NFkB;TWEAK;Toll Like Receptor 7/8 (TLR7/8) Cascade;double stranded rna induced gene expression;Interleukin-17 signaling;Signal Transduction;Signaling by Interleukins;p75NTR signals via NF-kB;influence of ras and rho proteins on g1 to s transition;role of egf receptor transactivation by gpcrs in cardiac hypertrophy;chaperones modulate interferon signaling pathway;trefoil factors initiate mucosal healing;signal transduction through il1r;tnf/stress related signaling;nf-kb signaling pathway;nfkb activation by nontypeable hemophilus influenzae;keratinocyte differentiation;toll-like receptor pathway;mapkinase signaling pathway;Cytokine Signaling in Immune system;Toll Like Receptor 9 (TLR9) Cascade;MyD88 cascade initiated on plasma membrane;Toll Like Receptor 10 (TLR10) Cascade;TICAM1, RIP1-mediated IKK complex recruitment ;Toll Like Receptor 3 (TLR3) Cascade;Toll Like Receptor 5 (TLR5) Cascade;B cell receptor signaling;ZBP1(DAI) mediated induction of type I IFNs;Toll-Like Receptors Cascades;Downstream TCR signaling;TCR signaling;NOD1/2 Signaling Pathway;Nucleotide-binding domain, leucine rich repeat containing receptor (NLR) signaling pathways;NF-kB activation through FADD/RIP-1 pathway mediated by caspase-8 and -10;TRAF6 mediated NF-kB activation;DDX58/IFIH1-mediated induction of interferon-alpha/beta;Activation of NF-kappaB in B cells;Signaling by the B Cell Receptor (BCR);Interleukin-1 signaling;CLEC7A (Dectin-1) signaling;C-type lectin receptors (CLRs);Fc epsilon receptor (FCERI) signaling;TCR;IRAK1 recruits IKK complex upon TLR7/8 or 9 stimulation;Innate Immune System;Immune System;Adaptive Immune System;inactivation of gsk3 by akt causes accumulation of b-catenin in alveolar macrophages;Downstream signaling events of B Cell Receptor (BCR);BCR;IL-1 NFkB;Antigen processing-Cross presentation;Class I MHC mediated antigen processing & presentation;ceramide signaling pathway;IL1;RIP-mediated NFkB activation via ZBP1;IL-7 signaling;TAK1 activates NFkB by phosphorylation and activation of IKKs complex;MAP3K8 (TPL2)-dependent MAPK1/3 activation;TNFR1-induced NFkappaB signaling pathway;MAP kinase activation;TRAF6 mediated induction of NFkB and MAP kinases upon TLR7/8 or 9 activation;TNF signaling;MyD88 dependent cascade initiated on endosome;Validated transcriptional targets of TAp63 isoforms;BCR signaling pathway;bone remodeling;JAK STAT pathway and regulation;IL11;p75NTR recruits signalling complexes;EPO signaling;NF-kB is activated and signals survival;Death Receptor Signalling;Regulation of TNFR1 signaling;p75 NTR receptor-mediated signalling;IL4;Leptin;FCERI mediated NF-kB activation;ER-Phagosome pathway;TSH;TNFalpha;Cytosolic sensors of pathogen-associated DNA ;IKK complex recruitment mediated by RIP1;TRIF(TICAM1)-mediated TLR4 signaling ;MyD88-independent TLR4 cascade ;Toll Like Receptor 4 (TLR4) Cascade;TNF;VEGF;Canonical NF-kappaB pathway;IRAK1 recruits IKK complex;MyD88:Mal cascade initiated on plasma membrane;Toll Like Receptor TLR1:TLR2 Cascade;RANKL;Toll Like Receptor TLR6:TLR2 Cascade;Toll Like Receptor 2 (TLR2) Cascade;GMCSF-mediated signaling events;mTOR signaling pathway;TRAIL signaling pathway;TNF receptor signaling pathway ;Fc-epsilon receptor I signaling in mast cells;Endogenous TLR signaling;TCR signaling in naïve CD8+ T cells;p75(NTR)-mediated signaling;FAS (CD95) signaling pathway;FoxO family signaling;IL1-mediated signaling events;TCR signaling in naïve CD4+ T cells;Atypical NF-kappaB pathway;Interleukin-1 family signaling;CD4 T cell receptor signaling-NFkB cascade;CD4 T cell receptor signaling (Consensus)

Recessive Scores

• pRec: 0.811

Intolerance Scores

• loftool: 0.698
• rvis_EVS: -0.75
• rvis_percentile_EVS: 13.58

Haploinsufficiency Scores

• pHI: 0.432
• hipred: Y
• hipred_score: 0.765
• ghis: 0.624

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.965

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Ikbkb
• Phenotype: normal phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); hematopoietic system phenotype; 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); liver/biliary system phenotype; embryo phenotype; immune system phenotype; limbs/digits/tail phenotype; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); digestive/alimentary phenotype; muscle phenotype; endocrine/exocrine gland phenotype; integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); growth/size/body region phenotype; cellular phenotype; homeostasis/metabolism phenotype

Zebrafish Information Network

• Gene name: ikbkb
• Affected structure: cell
• Phenotype tag: abnormal
• Phenotype quality: detached from

Gene ontology

• Biological process: stimulatory C-type lectin receptor signaling pathway;antigen processing and presentation of exogenous peptide antigen via MHC class I, TAP-dependent;MyD88-independent toll-like receptor signaling pathway;protein phosphorylation;inflammatory response;I-kappaB kinase/NF-kappaB signaling;I-kappaB phosphorylation;response to virus;regulation of tumor necrosis factor-mediated signaling pathway;viral process;peptidyl-serine phosphorylation;cortical actin cytoskeleton organization;tumor necrosis factor-mediated signaling pathway;negative regulation of myosin-light-chain-phosphatase activity;TRIF-dependent toll-like receptor signaling pathway;Fc-epsilon receptor signaling pathway;regulation of phosphorylation;negative regulation of apoptotic process;positive regulation of I-kappaB kinase/NF-kappaB signaling;innate immune response;positive regulation of transcription, DNA-templated;positive regulation of transcription by RNA polymerase II;T cell receptor signaling pathway;positive regulation of NF-kappaB transcription factor activity;stress-activated MAPK cascade;interleukin-1-mediated signaling pathway;cellular response to tumor necrosis factor;protein localization to plasma membrane;regulation of establishment of endothelial barrier;negative regulation of bicellular tight junction assembly
• Cellular component: nucleus;cytoplasm;cytosol;IkappaB kinase complex;cytoplasmic side of plasma membrane;CD40 receptor complex;membrane raft
• Molecular function: protein kinase activity;protein serine/threonine kinase activity;protein binding;ATP binding;IkappaB kinase activity;protein kinase binding;identical protein binding;protein homodimerization activity;protein heterodimerization activity;scaffold protein binding