IKBKB
inhibitor of nuclear factor kappa B kinase subunit beta, the group of I kappa B kinases|IKK complex
Basic information
Region (hg38): 8:42271302-42332460
Links
Phenotypes
GenCC
Source:
- 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:
| 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
- Severe combined immunodeficiency due to IKK2 deficiency (16 variants)
- Immunodeficiency 15a (1 variants)
- not provided (1 variants)
- IKBKB-related disorder (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 | 181 | 189 | ||||
| missense | 171 | 188 | ||||
| nonsense | 11 | |||||
| start loss | 0 | |||||
| frameshift | 10 | |||||
| inframe indel | 3 | |||||
| splice donor/acceptor (+/-2bp) | 4 | |||||
| splice region | 11 | 42 | 4 | 57 | ||
| non coding | 163 | 27 | 194 | |||
| Total | 16 | 7 | 184 | 353 | 39 |
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 (-) | ||
| 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 • Inborn genetic diseases | Uncertain significance (May 30, 2024) | ||
| 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:
| 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:
- 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