IRF2BP2

protein-coding

interferon regulatory factor 2 binding protein 2

Gene summary

This gene encodes an interferon regulatory factor-2 (IRF2) binding protein that interacts with the C-terminal transcriptional repression domain of IRF2. Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Jul 2008]

MANE transcript

NM_182972.3

Inheritance

ClinVar variants

P:7U:483B:285

Top phenotype

Immunodeficiency, common variable, 14

gnomAD constraint

pLI —, LoF o/e 0.1

Max pathogenic AF

—

Genomic locus

chr1:234,602,300-234,610,178

External References & Databases

Ensembl (ENSG00000168264)

Transcript & Mutation Effects

hg38 • Region Span ~7.9 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

immunodeficiency, common variable, 14STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0054691

Submitter: PanelApp Australia

immunodeficiency, common variable, 14LIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0054691

Submitter: Labcorp Genetics (formerly Invitae)

immunodeficiency, common variable, 14LIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0054691

Submitter: Ambry Genetics

immunodeficiency, common variable, 14LIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0054691

Submitter: ClinGen

IRF2BP2 was first reported in relation to autosomal dominant immunodeficiency, common variable, 14 (CVID 14) in 2016 (Keller MD, et al., 2016, PMID: 27016798). CVID is a clinically and genetically heterogeneous entity, primarily presenting as an antibody deficiency with low levels of serum IgG, IgA, and/or IgM, functional antibody deficiency, and recurrent sinopulmonary bacterial infections. In addition, non-infectious complications linked to underlying immune dysregulation are present in a subset of patients. One missense variant (Ser551Asn) has been reported in one proband in one publication (PMID: 27016798), segregating in two additional affected family members. An additional patient with the IRF2BP2 c.1180A>C; p.Thr394Pro variant has been reported in an individual affected with CIVD in an abstract for the American college of allergy, asthma & immunology 2018 annual scientific meeting (Joseph 2018; https://doi.org/10.1016/j.anai.2018.09.308). This gene-disease association is supported by its role as a transcriptional corepressor, participating in the adaptive immune response by influencing the maintenance, production, and secretion of cytokines (PMID: 21576369), and the alteration of B-cell maturation found in patient cells (PMID: 27016798). In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship.

Clinical Genomic Database (CGD)

Immunodeficiency, common variable, 14AD

Manifestation: Allergy/Immunology/Infectious

Intervention: Allergy/Immunology/Infectious

Rationale: Antiinfectious prophylaxis and early and aggressive treatment of infections may be beneficial

Refs: 27016798

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to IRF2BP2 variants in ClinVar

7 Conditions Cataloged

not providedTotal: 750

not specifiedTotal: 183

IRF2BP2-related disorderTotal: 37

Immunodeficiency, common variable, 14Total: 32

Varicella, severe recurrentTotal: 1

Immune deficiency, familial variableTotal: 1

Inborn error of immunityTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_182972.3. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous				270 clinvar	2 clinvar	272
missense			445 clinvar	13 clinvar		458
nonsense	1 clinvar	3 clinvar	14 clinvar			18
start loss						0
frameshift		3 clinvar	23 clinvar			26
splice donor/acceptor (+/-2bp)			1 clinvar			1
Total	1	6	483	283	2	775

Highest pathogenic variant AF is 8.894803e-7

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 12 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_182972.3	RefSeq	NP_892017.2	2	MANE Select
ENST00000366609.4	Ensembl	ENSP00000355568.3	2	MANE Select
NM_001077397.1	RefSeq	NP_001070865.1	2	Standard
ENST00000366610.7	Ensembl	ENSP00000355569.3	2	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

negative regulation of transcription by RNA polymerase II
immature B cell differentiation
positive regulation of transcription by RNA polymerase II

Molecular Function

RNA polymerase II regulatory region sequence-specific DNA binding
DNA-binding transcription activator activity, RNA polymerase II-specific
metal ion binding

Cellular Component

nucleus
nucleoplasm
cytoplasm

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000366609
Coding exons: 2
Length: 5257
Individuals with no LoFs: 0
Homozygous LoFs: 0
Heterozygous LoFs: 0
Defined: 0
p: 0.00

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.622	213	240	0.887	0.0000113	3624
Missense (PolyPhen)		84	107.36	0.78239		1304
Synonymous	-6.28	188	106	1.78	0.00000540	1263
Loss of Function	2.72	1	10.5	0.0951	4.53e-7	157

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0	0.0	absent
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Acts as a transcriptional corepressor in a IRF2- dependent manner; this repression is not mediated by histone deacetylase activities (PubMed:12799427). Represses the NFAT1- dependent transactivation of NFAT-responsive promoters (PubMed:21576369). Acts as a coactivator of VEGFA expression in cardiac and skeletal muscles (PubMed:20702774). Plays a role in immature B-cell differentiation (PubMed:27016798). {ECO:0000269|PubMed:12799427, ECO:0000269|PubMed:20702774, ECO:0000269|PubMed:21576369, ECO:0000269|PubMed:27016798}.;
Disease: DISEASE: Immunodeficiency, common variable, 14 (CVID14) [MIM:617765]: A primary immunodeficiency resulting in recurrent sinopulmonary infections since early childhood, and characterized by hypogammaglobulinemia with undetectable IgG and IgA, poor response to vaccination, and decreased levels of switched memory B cells. CVID14 inheritance is autosomal dominant. {ECO:0000269|PubMed:27016798}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.110

Essentials

Essential (CRISPR): E
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.992

Gene Damage Prediction

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