Immunodeficiency, common variable, 2

Summary

Immunodeficiency, common variable, 2 (MONDO:0009413) is a disease caused by TNFRSF13B (GenCC Strong), with 4 cohort genes.

At a glance

• Causal gene: TNFRSF13B (GenCC Strong)
• Cohort genes: 4
• ClinVar variants: 352

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	immunodeficiency, common variable, 2
Mondo ID	MONDO:0009413
OMIM	240500
DOID	DOID:0081145
UMLS	C3150354
MedGen	461704
GARD	0015184
Is cancer (heuristic)	no

Also known as: CVID2 · immunodeficiency, common variable, 2 · immunodeficiency, common variable, type 2

Data availability: 352 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › syndromic agammaglobulinemia › common variable immunodeficiency › immunodeficiency, common variable, 2

Related subtypes (15): immune deficiency, familial variable, 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, immunodeficiency, common variable, 10, 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

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

352 retrieved; paginated sample, class counts are floors:

171 uncertain significance, 104 likely benign, 27 pathogenic, 23 conflicting classifications of pathogenicity, 10 benign, 7 benign/likely benign, 5 pathogenic/likely pathogenic, 4 likely pathogenic, 1 conflicting classifications of pathogenicity; risk factor

ClinVar	Variant (HGVS)	Gene	Classification	Review
1071649	NM_012452.3(TNFRSF13B):c.552C>A (p.Cys184Ter)	TNFRSF13B	Pathogenic	criteria provided, multiple submitters, no conflicts
1379832	NM_012452.3(TNFRSF13B):c.62-2A>G	TNFRSF13B	Pathogenic	criteria provided, single submitter
1401351	NM_012452.3(TNFRSF13B):c.497del (p.Thr166fs)	TNFRSF13B	Pathogenic	criteria provided, single submitter
1422026	NM_012452.3(TNFRSF13B):c.25C>T (p.Arg9Ter)	TNFRSF13B	Pathogenic	criteria provided, single submitter
1436172	NM_012452.3(TNFRSF13B):c.61+2T>C	TNFRSF13B	Pathogenic	criteria provided, single submitter
1455440	NM_012452.3(TNFRSF13B):c.61+1G>A	TNFRSF13B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1456816	NM_012452.3(TNFRSF13B):c.298dup (p.Cys100fs)	TNFRSF13B	Pathogenic	criteria provided, single submitter
1974800	NM_012452.3(TNFRSF13B):c.306C>A (p.Tyr102Ter)	TNFRSF13B	Pathogenic	criteria provided, single submitter
203368	NM_012452.3(TNFRSF13B):c.492C>G (p.Tyr164Ter)	TNFRSF13B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2425818	NC_000017.10:g.(?16875309)(16875389_?)del	TNFRSF13B	Pathogenic	criteria provided, single submitter
265340	NM_012452.3(TNFRSF13B):c.431C>G (p.Ser144Ter)	TNFRSF13B	Pathogenic	criteria provided, multiple submitters, no conflicts
2778898	NM_012452.3(TNFRSF13B):c.91_92del (p.Met31fs)	TNFRSF13B	Pathogenic	criteria provided, single submitter
2780378	NM_012452.3(TNFRSF13B):c.355del (p.Arg119fs)	TNFRSF13B	Pathogenic	criteria provided, single submitter
322029	NM_012452.3(TNFRSF13B):c.204dup (p.Leu69fs)	TNFRSF13B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3243072	NC_000017.10:g.(?16852032)(16852317_?)del	TNFRSF13B	Pathogenic	criteria provided, single submitter
3243073	NC_000017.10:g.(?16842861)(16843845_?)del	TNFRSF13B	Pathogenic	criteria provided, single submitter
3677153	NM_012452.3(TNFRSF13B):c.246_265del (p.Leu83fs)	TNFRSF13B	Pathogenic	criteria provided, single submitter
3687684	NM_012452.3(TNFRSF13B):c.493_497dup (p.Leu167fs)	TNFRSF13B	Pathogenic	criteria provided, single submitter
3722490	NM_012452.3(TNFRSF13B):c.306C>G (p.Tyr102Ter)	TNFRSF13B	Pathogenic	criteria provided, single submitter
4531637	NM_012452.3(TNFRSF13B):c.141C>A (p.Cys47Ter)	TNFRSF13B	Pathogenic	criteria provided, single submitter
4777067	NM_012452.3(TNFRSF13B):c.452dup (p.Leu153fs)	TNFRSF13B	Pathogenic	criteria provided, single submitter
5306	NM_012452.2(TNFRSF13B):c.581_582delCCinsAA (p.Ser194Ter)	TNFRSF13B	Pathogenic	criteria provided, multiple submitters, no conflicts
5307	NM_012452.3(TNFRSF13B):c.431C>A (p.Ser144Ter)	TNFRSF13B	Pathogenic	criteria provided, single submitter
538707	NM_012452.3(TNFRSF13B):c.49del (p.Gln17fs)	TNFRSF13B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
647108	NM_012452.3(TNFRSF13B):c.95_96dup (p.Ser33fs)	TNFRSF13B	Pathogenic	criteria provided, single submitter
647267	NM_012452.3(TNFRSF13B):c.61+1G>T	TNFRSF13B	Pathogenic	criteria provided, multiple submitters, no conflicts
657318	NM_012452.3(TNFRSF13B):c.579C>A (p.Cys193Ter)	TNFRSF13B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
657940	NM_012452.3(TNFRSF13B):c.227_231del (p.Gly76fs)	TNFRSF13B	Pathogenic	criteria provided, single submitter
840923	NM_012452.3(TNFRSF13B):c.198C>A (p.Cys66Ter)	TNFRSF13B	Pathogenic	criteria provided, multiple submitters, no conflicts
853184	NM_012452.3(TNFRSF13B):c.62-1G>A	TNFRSF13B	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 4 · 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
TNFRSF13B	Strong	Autosomal recessive	immunodeficiency, common variable, 2	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TNFRSF13B	Orphanet:696907	Common variable immunodeficiency phenotype due to homozygous TACI deficiency
CD19	Orphanet:696881	Common variable immunodeficiency phenotype due to CD19/CD81 deficiency
CR2	Orphanet:536	Systemic lupus erythematosus
CR2	Orphanet:696894	Common variable immunodeficiency phenotype due to CD21 deficiency

Cohort genes → proteins

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TNFRSF13B	HGNC:18153	ENSG00000240505	O14836	Tumor necrosis factor receptor superfamily member 13B	gencc,clinvar
CD19	HGNC:1633	ENSG00000177455	P15391	B-lymphocyte antigen CD19	clinvar
CR2	HGNC:2336	ENSG00000117322	P20023	Complement receptor type 2	clinvar
EVPLL	HGNC:35236	ENSG00000214860	A8MZ36	Envoplakin-like protein	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
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.
CD19	B-lymphocyte antigen CD19	Functions as a coreceptor for the B-cell antigen receptor complex (BCR) on B-lymphocytes.
CR2	Complement receptor type 2	Serves as a receptor for various ligands including complement component CD3d, HNRNPU OR IFNA1.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.5

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
Complement	1	67.0×	0.045
Antibody/Immunoglobulin	1	7.3×	0.195
Other/Unknown	2	0.9×	0.769

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TNFRSF13B	Other/Unknown	no		TACI_Cys-rich-dom, TNFR_13B
CD19	Antibody/Immunoglobulin	yes		Ig_sub, Ig-like_dom, Ig-like_fold
CR2	Complement	yes		Sushi_SCR_CCP_dom, Sushi/SCR/CCP_sf, SEZ6_CSMD_C4BPB_Regulators
EVPLL	Other/Unknown	no		Plakin, Spectrin_PEPL/EVPL

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)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
spleen	3
olfactory bulb	1
type B pancreatic cell	1
lymph node	1
vermiform appendix	1
oocyte	1
secondary oocyte	1
esophagus mucosa	1
lower esophagus mucosa	1
primordial germ cell in gonad	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TNFRSF13B	158	tissue_specific	marker	type B pancreatic cell, olfactory bulb, spleen
CD19	164	tissue_specific	marker	spleen, lymph node, vermiform appendix
CR2	150	broad	marker	secondary oocyte, oocyte, spleen
EVPLL	80	broad	yes	lower esophagus mucosa, esophagus mucosa, primordial germ cell in gonad

Protein interactions among cohort

Intra-cohort edges: 2.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CD19	3,552
CR2	1,484
TNFRSF13B	1,333
EVPLL	538

Intra-cohort edges

A	B	Sources
CD19	CR2	biogrid_interaction, string_interaction
CR2	TNFRSF13B	string_interaction

Structural data

PDB: 3 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CR2	P20023	9
CD19	P15391	4
TNFRSF13B	O14836	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
EVPLL	A8MZ36	69.26

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 18. Enrichment computed across 4 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
Regulation of Complement cascade	2	155.4×	1e-03	CD19, CR2
Complement cascade	1	211.5×	0.026	CD19
TNFs bind their physiological receptors	1	131.3×	0.026	TNFRSF13B
PI3K/AKT Signaling in Cancer	1	122.8×	0.026	CD19
Antigen activates B Cell Receptor (BCR) leading to generation of second messengers	1	119.0×	0.026	CD19
Signaling by the B Cell Receptor (BCR)	1	115.3×	0.026	CD19
Negative regulation of the PI3K/AKT network	1	92.8×	0.028	CD19
Constitutive Signaling by Aberrant PI3K in Cancer	1	42.3×	0.053	CD19
PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling	1	32.3×	0.056	CD19
Intracellular signaling by second messengers	1	30.4×	0.056	CD19
Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell	1	29.1×	0.056	CD19
PIP3 activates AKT signaling	1	22.3×	0.066	CD19
Diseases of signal transduction by growth factor receptors and second messengers	1	18.9×	0.072	CD19
Adaptive Immune System	1	9.9×	0.125	CD19
Innate Immune System	1	8.5×	0.136	CD19
Disease	1	4.4×	0.227	CD19
Immune System	1	4.3×	0.227	CD19
Signal Transduction	1	3.4×	0.267	CD19

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
B cell proliferation	2	240.7×	6e-04	CD19, CR2
B-1 B cell differentiation	1	2106.5×	0.006	CD19
regulation of B cell activation	1	1404.3×	0.006	CD19
B cell proliferation involved in immune response	1	702.2×	0.006	CD19
antigen receptor-mediated signaling pathway	1	702.2×	0.006	CD19
regulation of B cell receptor signaling pathway	1	702.2×	0.006	CD19
negative regulation of complement activation, classical pathway	1	601.9×	0.006	CR2
T cell mediated immunity	1	247.8×	0.010	CR2
complement activation, alternative pathway	1	247.8×	0.010	CR2
negative regulation of B cell proliferation	1	234.1×	0.010	TNFRSF13B
intermediate filament cytoskeleton organization	1	234.1×	0.010	EVPLL
immunoglobulin mediated immune response	1	175.5×	0.012	CD19
B cell homeostasis	1	140.4×	0.013	TNFRSF13B
complement activation, classical pathway	1	135.9×	0.013	CR2
positive regulation of release of sequestered calcium ion into cytosol	1	123.9×	0.013	CD19
B cell activation	1	113.9×	0.014	CR2
symbiont entry into host cell	1	100.3×	0.014	CR2
B cell receptor signaling pathway	1	100.3×	0.014	CD19
type I interferon-mediated signaling pathway	1	86.0×	0.015	CR2
hematopoietic progenitor cell differentiation	1	59.3×	0.021	TNFRSF13B
B cell differentiation	1	54.7×	0.022	CR2
adaptive immune response	1	21.1×	0.053	TNFRSF13B
positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	1	19.6×	0.054	CD19
cell surface receptor signaling pathway	1	16.0×	0.064	TNFRSF13B
immune response	1	11.8×	0.082	CR2

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 4

Druggability breadth: 1 of 4 evidence-associated genes (25%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TNFRSF13B	0	0
CD19	0	0
CR2	0	0
EVPLL	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

0 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.

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	2	CD19, CR2
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	TNFRSF13B, EVPLL

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
TNFRSF13B	0	—
CD19	0	—
CR2	0	—
EVPLL	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.