NFKB2

nuclear factor kappa B subunit 2, the group of IPT domain containing|NF-kappa B complex subunits|Ankyrin repeat domain containing

Basic information

Region (hg38): 10:102394110-102402524

Links

ENSG00000077150 ∙ NCBI:4791 ∙ OMIM:164012 ∙ HGNC:7795 ∙ Uniprot:Q00653 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• immunodeficiency, common variable, 10 (Moderate), mode of inheritance: AD
• common variable immunodeficiency (Supportive), mode of inheritance: AD
• deficiency in anterior pituitary function - variable immunodeficiency syndrome (Supportive), mode of inheritance: AD
• immunodeficiency, common variable, 10 (Strong), mode of inheritance: AD
• immunodeficiency, common variable, 10 (Definitive), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Immunodeficiency, common variable, 10	AD	Allergy/Immunology/Infectious; Endocrine	Individuals have been described with immunodeficiency and recurrent infections, and antiinfectious prophylaxis and early and aggressive treatment of infections may be beneficial; Central adrenal insufficiency has been described, and medical management (with glucocorticoid and mineralocorticoid replacement) has been described as beneficial	Allergy/Immunology/Infectious; Endocrine; Renal	24140114; 24888602; 25237204; 25524009; 31417880

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the NFKB2 gene.

• Immunodeficiency, common variable, 10 (3 variants)
• not provided (3 variants)
• Inherited Immunodeficiency Diseases (3 variants)
• Common variable immunodeficiency (1 variants)
• not specified (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the NFKB2 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	162	13	179
missense		1	251	3	2	257
nonsense	4	1	1			6
start loss						0
frameshift	1	3	6			10
inframe indel			3			3
splice donor/acceptor (+/-2bp)	1	1	5			7
splice region			23	26		49
non coding			5	112	21	138
Total	6	6	275	277	36

Variants in NFKB2

This is a list of pathogenic ClinVar variants found in the NFKB2 region.

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

Position	Type	Phenotype	Significance	ClinVar
10-102395415-G-A			Benign (Aug 01, 2022)
10-102395637-C-A			Benign (Jul 01, 2022)
10-102395950-G-T		NFKB2-related disorder	Likely benign (Sep 21, 2023)
10-102395963-G-A		Immunodeficiency, common variable, 10	Uncertain significance (Oct 21, 2019)
10-102395968-T-C		Immunodeficiency, common variable, 10	Likely benign (Jan 24, 2024)
10-102395972-T-G		Immunodeficiency, common variable, 10	Uncertain significance (Jul 20, 2023)
10-102395973-A-G		Immunodeficiency, common variable, 10 • NFKB2-related disorder	Uncertain significance (Jan 16, 2024)
10-102395993-G-A		Immunodeficiency, common variable, 10	Benign/Likely benign (Jan 29, 2024)
10-102395995-C-T		Immunodeficiency, common variable, 10	Likely benign (Apr 03, 2022)
10-102395998-C-T		Immunodeficiency, common variable, 10	Likely benign (Feb 19, 2022)
10-102396235-A-T		Immunodeficiency, common variable, 10	Likely benign (Feb 08, 2022)
10-102396238-C-G		Immunodeficiency, common variable, 10	Likely benign (Oct 18, 2022)
10-102396246-A-G		Immunodeficiency, common variable, 10	Likely benign (Nov 27, 2023)
10-102396253-G-C		Immunodeficiency, common variable, 10	Uncertain significance (Jan 15, 2024)
10-102396258-G-A		Immunodeficiency, common variable, 10	Likely benign (Dec 11, 2023)
10-102396259-G-A		Immunodeficiency, common variable, 10	Uncertain significance (Aug 19, 2023)
10-102396260-A-G		Immunodeficiency, common variable, 10	Uncertain significance (Feb 14, 2023)
10-102396265-A-G		NFKB2-related disorder	Uncertain significance (Oct 09, 2023)
10-102396271-G-A		Immunodeficiency, common variable, 10	Benign (Jan 29, 2024)
10-102396276-T-C		Immunodeficiency, common variable, 10	Likely benign (Nov 04, 2021)
10-102396279-T-G		Immunodeficiency, common variable, 10	Uncertain significance (Aug 04, 2023)
10-102396282-T-C		Immunodeficiency, common variable, 10	Likely benign (Sep 17, 2023)
10-102396293-A-G		Immunodeficiency, common variable, 10	Uncertain significance (Aug 19, 2023)
10-102396297-C-T		Immunodeficiency, common variable, 10	Likely benign (Jan 11, 2024)
10-102396305-T-C		Inborn genetic diseases • Immunodeficiency, common variable, 10	Uncertain significance (May 23, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
NFKB2	protein_coding	protein_coding	ENST00000369966	22	8415

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.00	0.00000448	124746	0	53	124799	0.000212

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	3.94	265	517	0.513	0.0000303	5654
Missense in Polyphen		44	159.46	0.27593		1741
Synonymous	2.10	175	214	0.818	0.0000126	1903
Loss of Function	6.00	3	47.7	0.0629	0.00000269	504

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00170	0.00169
Ashkenazi Jewish	0.00	0.00
East Asian	0.0000560	0.0000556
Finnish	0.0000949	0.0000928
European (Non-Finnish)	0.000134	0.000132
Middle Eastern	0.0000560	0.0000556
South Asian	0.000164	0.000163
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: NF-kappa-B is a pleiotropic transcription factor present in almost all cell types and is the endpoint of a series of signal transduction events that are initiated by a vast array of stimuli related to many biological processes such as inflammation, immunity, differentiation, cell growth, tumorigenesis and apoptosis. NF-kappa-B is a homo- or heterodimeric complex formed by the Rel-like domain-containing proteins RELA/p65, RELB, NFKB1/p105, NFKB1/p50, REL and NFKB2/p52. The dimers bind at kappa-B sites in the DNA of their target genes and the individual dimers have distinct preferences for different kappa-B sites that they can bind with distinguishable affinity and specificity. Different dimer combinations act as transcriptional activators or repressors, respectively. NF-kappa-B is controlled by various mechanisms of post-translational modification and subcellular compartmentalization as well as by interactions with other cofactors or corepressors. NF-kappa-B complexes are held in the cytoplasm in an inactive state complexed with members of the NF- kappa-B inhibitor (I-kappa-B) family. In a conventional activation pathway, I-kappa-B is phosphorylated by I-kappa-B kinases (IKKs) in response to different activators, subsequently degraded thus liberating the active NF-kappa-B complex which translocates to the nucleus. In a non-canonical activation pathway, the MAP3K14- activated CHUK/IKKA homodimer phosphorylates NFKB2/p100 associated with RelB, inducing its proteolytic processing to NFKB2/p52 and the formation of NF-kappa-B RelB-p52 complexes. The NF-kappa-B heterodimeric RelB-p52 complex is a transcriptional activator. The NF-kappa-B p52-p52 homodimer is a transcriptional repressor. NFKB2 appears to have dual functions such as cytoplasmic retention of attached NF-kappa-B proteins by p100 and generation of p52 by a cotranslational processing. The proteasome-mediated process ensures the production of both p52 and p100 and preserves their independent function. p52 binds to the kappa-B consensus sequence 5'-GGRNNYYCC-3', located in the enhancer region of genes involved in immune response and acute phase reactions. p52 and p100 are respectively the minor and major form; the processing of p100 being relatively poor. Isoform p49 is a subunit of the NF-kappa-B protein complex, which stimulates the HIV enhancer in synergy with p65. In concert with RELB, regulates the circadian clock by repressing the transcriptional activator activity of the CLOCK- ARNTL/BMAL1 heterodimer. {ECO:0000269|PubMed:7925301}.
• Disease: DISEASE: Note=A chromosomal aberration involving NFKB2 is found in a case of B-cell non Hodgkin lymphoma (B-NHL). Translocation t(10;14)(q24;q32) with IGHA1. The resulting oncogene is also called Lyt-10C alpha variant.; DISEASE: Note=A chromosomal aberration involving NFKB2 is found in a cutaneous T-cell leukemia (C-TCL) cell line. This rearrangement produces the p80HT gene which codes for a truncated 80 kDa protein (p80HT).; DISEASE: Note=In B-cell leukemia (B-CLL) cell line, LB40 and EB308, can be found after heterogeneous chromosomal aberrations, such as internal deletions.; DISEASE: Immunodeficiency, common variable, 10 (CVID10) [MIM:615577]: A primary immunodeficiency characterized by childhood-onset of recurrent infections, hypogammaglobulinemia, and decreased numbers of memory and marginal zone B-cells. Some patients may develop autoimmune features and have circulating autoantibodies. An unusual feature is central adrenal insufficiency. {ECO:0000269|PubMed:24140114, ECO:0000269|PubMed:25524009}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Legionellosis - Homo sapiens (human);Breast cancer - Homo sapiens (human);HTLV-I infection - Homo sapiens (human);C-type lectin receptor signaling pathway - Homo sapiens (human);MAPK signaling pathway - Homo sapiens (human);Pathways in cancer - Homo sapiens (human);Viral carcinogenesis - Homo sapiens (human);Osteoclast differentiation - Homo sapiens (human);NF-kappa B signaling pathway - Homo sapiens (human);Epstein-Barr virus infection - Homo sapiens (human);EGFR Inhibitor Pathway, Pharmacodynamics;Tacrolimus/Cyclosporine Pathway, Pharmacodynamics;Intracellular Signalling Through Adenosine Receptor A2b and Adenosine;Intracellular Signalling Through Adenosine Receptor A2a and Adenosine;Regulation of toll-like receptor signaling pathway;Selenium Micronutrient Network;Vitamin B12 Metabolism;Folate Metabolism;RANKL-RANK (Receptor activator of NFKB (ligand)) Signaling Pathway;TNF related weak inducer of apoptosis (TWEAK) Signaling Pathway;Neural Crest Differentiation;Thymic Stromal LymphoPoietin (TSLP) Signaling Pathway;TNF alpha Signaling Pathway;EBV LMP1 signaling;Glucocorticoid Receptor Pathway;Nuclear Receptors Meta-Pathway;Photodynamic therapy-induced NF-kB survival signaling;MAPK Signaling Pathway;Toll-like Receptor Signaling;ApoE and miR-146 in inflammation and atherosclerosis;Protein alkylation leading to liver fibrosis;Sudden Infant Death Syndrome (SIDS) Susceptibility Pathways;DNA Damage Response (only ATM dependent);Toll-like Receptor Signaling Pathway;TWEAK;Toll Like Receptor 7/8 (TLR7/8) Cascade;Signaling by Interleukins;NIK-->noncanonical NF-kB signaling;TNFR2 non-canonical NF-kB pathway;Cytokine Signaling in Immune system;Toll Like Receptor 9 (TLR9) Cascade;MyD88 cascade initiated on plasma membrane;Toll Like Receptor 10 (TLR10) Cascade;Toll Like Receptor 3 (TLR3) Cascade;Toll Like Receptor 5 (TLR5) Cascade;ZBP1(DAI) mediated induction of type I IFNs;Toll-Like Receptors Cascades;TRAF6 mediated NF-kB activation;DDX58/IFIH1-mediated induction of interferon-alpha/beta;DEx/H-box helicases activate type I IFN and inflammatory cytokines production ;Interleukin-1 signaling;Dectin-1 mediated noncanonical NF-kB signaling;CLEC7A (Dectin-1) signaling;PKMTs methylate histone lysines;C-type lectin receptors (CLRs);Chromatin modifying enzymes;Innate Immune System;Immune System;RIP-mediated NFkB activation via ZBP1;TAK1 activates NFkB by phosphorylation and activation of IKKs complex;TRAF6 mediated induction of NFkB and MAP kinases upon TLR7/8 or 9 activation;MyD88 dependent cascade initiated on endosome;Chromatin organization;TNFalpha;Cytosolic sensors of pathogen-associated DNA ;TRIF(TICAM1)-mediated TLR4 signaling ;MyD88-independent TLR4 cascade ;Toll Like Receptor 4 (TLR4) Cascade;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;Interleukin-1 processing;Alternative NF-kappaB pathway;IL12-mediated signaling events;Interleukin-1 family signaling;TSLP (Consensus)

Recessive Scores

• pRec: 0.476

Intolerance Scores

• loftool: 0.180
• rvis_EVS: -0.78
• rvis_percentile_EVS: 12.88

Haploinsufficiency Scores

• pHI: 0.822
• hipred: Y
• hipred_score: 0.825
• ghis: 0.602

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.947

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Nfkb2
• Phenotype: renal/urinary system phenotype; skeleton phenotype; immune system phenotype; digestive/alimentary phenotype; hematopoietic system 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); reproductive system phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); liver/biliary system phenotype; respiratory system phenotype; homeostasis/metabolism phenotype; cellular phenotype; craniofacial phenotype; endocrine/exocrine gland phenotype; growth/size/body region 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)

Zebrafish Information Network

• Gene name: nfkb2
• Affected structure: intersegmental vessel
• Phenotype tag: abnormal
• Phenotype quality: immature

Gene ontology

• Biological process: follicular dendritic cell differentiation;germinal center formation;regulation of transcription, DNA-templated;aging;extracellular matrix organization;positive regulation of type I interferon production;response to lipopolysaccharide;response to cytokine;NIK/NF-kappaB signaling;positive regulation of transcription by RNA polymerase II;rhythmic process;spleen development;positive regulation of NF-kappaB transcription factor activity
• Cellular component: nucleus;nucleoplasm;cytoplasm;cytosol;Bcl3/NF-kappaB2 complex
• Molecular function: RNA polymerase II proximal promoter sequence-specific DNA binding;DNA-binding transcription factor activity, RNA polymerase II-specific;DNA-binding transcription activator activity, RNA polymerase II-specific;DNA-binding transcription factor activity;transcription coactivator activity;protein binding