Immunodeficiency, common variable, 10

Summary

Immunodeficiency, common variable, 10 (MONDO:0014260) is a disease caused by NFKB2 (GenCC Strong), with 3 cohort genes.

At a glance

• Causal gene: NFKB2 (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 797

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	immunodeficiency, common variable, 10
Mondo ID	MONDO:0014260
OMIM	615577
DOID	DOID:0081152
UMLS	C3809991
MedGen	816321
GARD	0015990
Is cancer (heuristic)	no

Also known as: common variable immunodeficiency caused by mutation in NFKB2 · CVID10 · immunodeficiency, common variable, 10 · immunodeficiency, common variable, type 10 · NFKB2 common variable immunodeficiency

Data availability: 797 ClinVar variants · 3 GenCC gene-disease records.

Disease family

An umbrella term covering 1 Mondo subtype.

Classification path: disease › human disease › disease by body system or component › syndromic disease › syndromic agammaglobulinemia › common variable immunodeficiency › immunodeficiency, common variable, 10

Related subtypes (15): immune deficiency, familial variable, immunodeficiency, common variable, 2, immunodeficiency, common variable, 1, immunodeficiency, common variable, 3, immunodeficiency, common variable, 4, immunodeficiency, common variable, 5, immunodeficiency, common variable, 6, immunodeficiency, common variable, 7, combined immunodeficiency due to LRBA deficiency, IL21-related infantile inflammatory bowel disease, immunodeficiency, common variable, 12, pancytopenia due to IKZF1 mutations, immunodeficiency, common variable, 14, immunodeficiency, common variable, due to APRIL deficiency, immunodeficiency, common variable, 15

Subtypes (1): deficiency in anterior pituitary function - variable immunodeficiency syndrome

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

600 retrieved; paginated sample, class counts are floors:

304 likely benign, 265 uncertain significance, 18 benign, 7 conflicting classifications of pathogenicity, 3 pathogenic, 1 benign/likely benign, 1 pathogenic/likely pathogenic, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1409384	NM_001322934.2(NFKB2):c.2602_2605dup (p.Gly869fs)	NFKB2	Pathogenic	criteria provided, single submitter
155764	NM_001322934.2(NFKB2):c.2556_2563del (p.Arg853fs)	NFKB2	Pathogenic	no assertion criteria provided
155765	NM_001322934.2(NFKB2):c.2594A>G (p.Asp865Gly)	NFKB2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2915458	NM_001322934.2(NFKB2):c.2596_2597del (p.Ser866fs)	NFKB2	Pathogenic	criteria provided, single submitter
2432214	NM_001322934.2(NFKB2):c.1359_1363dup (p.Gln455fs)	NFKB2	Likely pathogenic	criteria provided, single submitter
1000283	NM_001322934.2(NFKB2):c.2464G>A (p.Glu822Lys)	NFKB2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1482053	NM_001322934.2(NFKB2):c.1534C>T (p.His512Tyr)	NFKB2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
155766	NM_001322934.2(NFKB2):c.2600C>T (p.Ala867Val)	NFKB2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1938189	NM_001322934.2(NFKB2):c.1470-7C>T	NFKB2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1980215	NM_001322934.2(NFKB2):c.502+16dup	NFKB2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2080578	NM_001322934.2(NFKB2):c.2677G>A (p.Gly893Arg)	NFKB2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2431934	NM_001322934.2(NFKB2):c.2598T>C (p.Ser866=)	NFKB2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1006763	NM_001322934.2(NFKB2):c.662A>G (p.Lys221Arg)	LOC121815964	Uncertain significance	criteria provided, single submitter
1022376	NM_001322934.2(NFKB2):c.673dup (p.Ala225fs)	LOC121815964	Uncertain significance	criteria provided, single submitter
1435511	NM_001322934.2(NFKB2):c.736G>A (p.Val246Ile)	LOC121815964	Uncertain significance	criteria provided, single submitter
1464360	NM_001322934.2(NFKB2):c.722G>A (p.Arg241Gln)	LOC121815964	Uncertain significance	criteria provided, single submitter
1965649	NM_001322934.2(NFKB2):c.710C>T (p.Ala237Val)	LOC121815964	Uncertain significance	criteria provided, single submitter
1996426	NM_001322934.2(NFKB2):c.719_720del (p.Val240fs)	LOC121815964	Uncertain significance	criteria provided, single submitter
3677032	NM_001322934.2(NFKB2):c.727G>A (p.Gly243Arg)	LOC121815964	Uncertain significance	criteria provided, single submitter
1497588	NM_001322934.2(NFKB2):c.62A>G (p.Asn21Ser)	LOC130004598	Uncertain significance	criteria provided, multiple submitters, no conflicts
1517693	NM_001322934.2(NFKB2):c.22G>C (p.Gly8Arg)	LOC130004598	Uncertain significance	criteria provided, multiple submitters, no conflicts
2166209	NM_001322934.2(NFKB2):c.48T>G (p.Asp16Glu)	LOC130004598	Uncertain significance	criteria provided, single submitter
2754038	NM_001322934.2(NFKB2):c.28G>A (p.Asp10Asn)	LOC130004598	Uncertain significance	criteria provided, single submitter
2787729	NM_001322934.2(NFKB2):c.29A>G (p.Asp10Gly)	LOC130004598	Uncertain significance	criteria provided, single submitter
3683388	NM_001322934.2(NFKB2):c.26T>G (p.Leu9Arg)	LOC130004598	Uncertain significance	criteria provided, multiple submitters, no conflicts
3729857	NM_001322934.2(NFKB2):c.65C>T (p.Ser22Phe)	LOC130004598	Uncertain significance	criteria provided, single submitter
1008266	NM_001322934.2(NFKB2):c.1183A>C (p.Met395Leu)	LOC130004599	Uncertain significance	criteria provided, single submitter
1028506	NM_001322934.2(NFKB2):c.1297G>C (p.Glu433Gln)	LOC130004599	Uncertain significance	criteria provided, multiple submitters, no conflicts
1338871	NM_001322934.2(NFKB2):c.1210G>A (p.Gly404Arg)	LOC130004599	Uncertain significance	criteria provided, multiple submitters, no conflicts
1346579	NM_001322934.2(NFKB2):c.1258G>A (p.Ala420Thr)	LOC130004599	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 5 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
NFKB2	Strong	Autosomal dominant	immunodeficiency, common variable, 10	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
NFKB2	Orphanet:293978	Deficiency in anterior pituitary function-variable immunodeficiency syndrome
STIM1	Orphanet:2593	Tubular aggregate myopathy
STIM1	Orphanet:317430	Combined immunodeficiency due to STIM1 deficiency
STIM1	Orphanet:3204	Stormorken-Sjaastad-Langslet syndrome
TNFRSF13B	Orphanet:696907	Common variable immunodeficiency phenotype due to homozygous TACI deficiency

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
NFKB2	HGNC:7795	ENSG00000077150	Q00653	Nuclear factor NF-kappa-B p100 subunit	gencc,clinvar
STIM1	HGNC:11386	ENSG00000167323	Q13586	Stromal interaction molecule 1	clinvar
TNFRSF13B	HGNC:18153	ENSG00000240505	O14836	Tumor necrosis factor receptor superfamily member 13B	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
NFKB2	Nuclear factor NF-kappa-B p100 subunit	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 infl…
STIM1	Stromal interaction molecule 1	Acts as a Ca(2+) sensor that gates two major inward rectifying Ca(2+) channels at the plasma membrane: Ca(2+) release-activated Ca(2+) (CRAC) channels and arachidonate-regulated Ca(2+)-selective (ARC) channels.
TNFRSF13B	Tumor necrosis factor receptor superfamily member 13B	Receptor for TNFSF13/APRIL and TNFSF13B/TALL1/BAFF/BLYS that binds both ligands with similar high affinity.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 2 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Transcription factor	1	2.8×	0.587
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
NFKB2	Transcription factor	no		NFkB/Dor, Death_dom, Ankyrin_rpt
STIM1	Other/Unknown	no		SAM, SAM/pointed_sf, SOAR_STIM1/2
TNFRSF13B	Other/Unknown	no		TACI_Cys-rich-dom, TNFR_13B

Expression context

Cohort genes with no expression data: 0.

3 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
spleen	2
granulocyte	1
muscle layer of sigmoid colon	1
gastrocnemius	1
hindlimb stylopod muscle	1
muscle of leg	1
olfactory bulb	1
type B pancreatic cell	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
NFKB2	221	ubiquitous	marker	granulocyte, muscle layer of sigmoid colon, spleen
STIM1	237	ubiquitous	marker	gastrocnemius, muscle of leg, hindlimb stylopod muscle
TNFRSF13B	158	tissue_specific	marker	type B pancreatic cell, olfactory bulb, spleen

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NFKB2	4,041
STIM1	3,074
TNFRSF13B	1,333

Structural data

PDB: 3 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
NFKB2	Q00653	11
STIM1	Q13586	6
TNFRSF13B	O14836	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 25. Enrichment computed across 3 evidence-associated genes (3 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
DEx/H-box helicases activate type I IFN and inflammatory cytokines production	1	543.8×	0.014	NFKB2
IkBA variant leads to EDA-ID	1	543.8×	0.014	NFKB2
Interleukin-1 processing	1	423.0×	0.014	NFKB2
SUMOylation of immune response proteins	1	317.2×	0.014	NFKB2
Elevation of cytosolic Ca2+ levels	1	237.9×	0.014	STIM1
Platelet calcium homeostasis	1	237.9×	0.014	STIM1
RIP-mediated NFkB activation via ZBP1	1	223.9×	0.014	NFKB2
The NLRP3 inflammasome	1	223.9×	0.014	NFKB2
TRAF6 mediated NF-kB activation	1	152.3×	0.017	NFKB2
Purinergic signaling in leishmaniasis infection	1	141.0×	0.017	NFKB2
TNFs bind their physiological receptors	1	131.3×	0.017	TNFRSF13B
Antigen activates B Cell Receptor (BCR) leading to generation of second messengers	1	119.0×	0.017	STIM1
Signaling by the B Cell Receptor (BCR)	1	115.3×	0.017	STIM1
TAK1-dependent IKK and NF-kappa-B activation	1	100.2×	0.018	NFKB2
Platelet homeostasis	1	92.8×	0.018	STIM1
NIK–>noncanonical NF-kB signaling	1	76.1×	0.020	NFKB2
Dectin-1 mediated noncanonical NF-kB signaling	1	71.8×	0.020	NFKB2
Ion homeostasis	1	68.0×	0.020	STIM1
PKMTs methylate histone lysines	1	53.6×	0.024	NFKB2
Cardiac conduction	1	36.2×	0.033	STIM1
Regulation of PD-L1(CD274) transcription	1	36.2×	0.033	NFKB2
Muscle contraction	1	25.7×	0.044	STIM1
Hemostasis	1	12.0×	0.088	STIM1
Adaptive Immune System	1	9.9×	0.101	STIM1
Immune System	1	4.3×	0.214	STIM1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
follicular dendritic cell differentiation	1	2808.7×	0.007	NFKB2
activation of store-operated calcium channel activity	1	1123.5×	0.007	STIM1
positive regulation of adenylate cyclase activity	1	1123.5×	0.007	STIM1
store-operated calcium entry	1	561.7×	0.008	STIM1
germinal center formation	1	561.7×	0.008	NFKB2
enamel mineralization	1	401.2×	0.008	STIM1
detection of calcium ion	1	374.5×	0.008	STIM1
regulation of store-operated calcium entry	1	351.1×	0.008	STIM1
negative regulation of B cell proliferation	1	312.1×	0.008	TNFRSF13B
non-canonical NF-kappaB signal transduction	1	280.9×	0.008	NFKB2
regulation of calcium ion transport	1	267.5×	0.008	STIM1
B cell homeostasis	1	187.2×	0.011	TNFRSF13B
spleen development	1	133.8×	0.014	NFKB2
response to cytokine	1	124.8×	0.014	NFKB2
canonical NF-kappaB signal transduction	1	122.1×	0.014	NFKB2
rhythmic process	1	83.8×	0.019	NFKB2
hematopoietic progenitor cell differentiation	1	79.1×	0.019	TNFRSF13B
intracellular calcium ion homeostasis	1	48.4×	0.028	STIM1
response to lipopolysaccharide	1	41.6×	0.030	NFKB2
extracellular matrix organization	1	40.7×	0.030	NFKB2
positive regulation of angiogenesis	1	38.5×	0.031	STIM1
adaptive immune response	1	28.1×	0.040	TNFRSF13B
cell surface receptor signaling pathway	1	21.4×	0.050	TNFRSF13B
regulation of DNA-templated transcription	1	10.5×	0.096	NFKB2
positive regulation of transcription by RNA polymerase II	1	5.0×	0.188	NFKB2

Therapeutics

Drug target analysis

Approved (phase 4): 2 · Phase ≥3: 2 · Phased (≥1): 2 · Undrugged: 1

Druggability breadth: 2 of 3 evidence-associated genes (67%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
NFKB2	INDOPROFEN
STIM1	TERIFLUNOMIDE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
NFKB2	15	4
STIM1	2	4
TNFRSF13B	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
INDOPROFEN	4	NFKB2
VAMOROLONE	4	NFKB2
BORTEZOMIB	4	NFKB2
DEXAMETHASONE	4	NFKB2
SULFASALAZINE	4	NFKB2
TERIFLUNOMIDE	4	STIM1
CURCUMIN	3	NFKB2
RESVERATROL	3	NFKB2
IXAZOMIB	3	NFKB2
WITHANOLIDE D	3	NFKB2
TRIPTOLIDE	3	NFKB2
FRENTIZOLE	2	NFKB2
LAPACHONE	2	NFKB2
SANGUINARIUM	2	NFKB2
ZEGOCRACTIN	2	STIM1
AS-602868	1	NFKB2
WITHAFERIN A	1	NFKB2

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
NFKB2	230	Binding:226, Functional:4
STIM1	35	Binding:33, Functional:1, ADMET:1

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
NFKB2	230

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

17 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
INDOPROFEN	4	NFKB2
VAMOROLONE	4	NFKB2
BORTEZOMIB	4	NFKB2
DEXAMETHASONE	4	NFKB2
SULFASALAZINE	4	NFKB2
TERIFLUNOMIDE	4	STIM1
CURCUMIN	3	NFKB2
RESVERATROL	3	NFKB2
IXAZOMIB	3	NFKB2
WITHANOLIDE D	3	NFKB2
TRIPTOLIDE	3	NFKB2
FRENTIZOLE	2	NFKB2
LAPACHONE	2	NFKB2
SANGUINARIUM	2	NFKB2
ZEGOCRACTIN	2	STIM1
AS-602868	1	NFKB2
WITHAFERIN A	1	NFKB2

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	2	NFKB2, STIM1
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	TNFRSF13B

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
TNFRSF13B	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.