CR2

protein-coding

complement C3d receptor 2, the group of CD molecules|Sushi domain containing|Complement system regulators and receptors

Gene summary

This gene encodes a membrane protein, which functions as a receptor for Epstein-Barr virus (EBV) binding on B and T lymphocytes. Genetic variations in this gene are associated with susceptibility to systemic lupus erythematosus type 9 (SLEB9). Alternatively spliced transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Sep 2009]

MANE transcript

NM_001006658.3

Inheritance

ClinVar variants

P:71U:412B:244

Top phenotype

Common variable immune deficiency, 7

gnomAD constraint

pLI —, LoF o/e 0.67

Max pathogenic AF

—

Genomic locus

chr1:207,453,024-207,489,895

External References & Databases

Ensembl (ENSG00000117322)

Transcript & Mutation Effects

hg38 • Region Span ~36.9 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

systemic lupus erythematosusSUPPORTIVE

Inheritance Pattern: Unknown

Disease ID:MONDO:0007915

Submitter: Orphanet

immunodeficiency, common variable, 7DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013862

Submitter: ClinGen

CR2, also referred to as CD21, was first reported in relation to autosomal recessive common variable immunodeficiency (CVID; OMIM # 614699) in 2012 (Thiel J et al., PMID: 22035880). CR2-associated CVID is a heterogeneous disorder characterized by hypogammaglobulinemia with some patients also presenting with recurrent infections, particularly respiratory infections. Importantly, individuals carrying biallelic pathogenic CR2 variants may present with the immunological phenotype of hypogammaglobulinemia and low levels of class-switched B cells in the absence of a clinical phenotype, such as recurrent infections (PMID: 30075290). It is currently unknown what proportion of affected individuals are currently asymptomatic or how likely they are to present with a clinical phenotype at a later age. Five variants (nonsense, frameshift, and canonical splice site) found that have been reported in three unrelated probands (and four probands total) as either compound heterozygous or homozygous in three publications are included in this curation (PMIDs: 22035880, 26325596, 28499783). The mechanism of pathogenicity appears to be loss of function. This gene-disease association is also supported by animal models, expression studies, and in vitro functional assays (PMIDs: 6234356, 8622941, 8624815, 1702139, 12479818, 22035880, 26325596). CR2 has been shown to be expressed on the majority of circulating mature human B cells and human follicular dendritic cells (PMID: 6234356, 2471772) and is part of the B-cell receptor complex (PMID: 1702139). CD19 (as well as CD81) is also a member of the B-cell receptor complex and has also been associated with common variable immunodeficiency (OMIM # 613493). Mouse models lacking expression of CR2/CR1 have decreased levels of antibody, particularly IgG, and have increased susceptibility to infection (PMIDs: 8622941, 8624815, 12479818). Expression of human CR2 in CR2/CR1-/- mice rescues secondary responses to T-dependent antigen in CR2/CR1-/- mice (PMID: 21269698). B cells from patients with CR2-associated CVID decreased responses to antigen and AID expression (PMIDs: 22035880, 26325596). In summary, CR2 is definitively associated with autosomal recessive CVID. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. Notably, this curation does not assess the reported relationship between CR2 and susceptibility to systemic lupus erythematosus (OMIM # 610927).

immunodeficiency, common variable, 7STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013862

Submitter: Labcorp Genetics (formerly Invitae)

immunodeficiency, common variable, 7MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0013862

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Common variable immune deficiency, 7AR

Manifestation: Allergy/Immunology/Infectious

Intervention: Allergy/Immunology/Infectious

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

Refs: 22035880

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CR2 variants in ClinVar

9 Conditions Cataloged

Immunodeficiency, common variable, 7Total: 763

Inborn genetic diseasesTotal: 146

not providedTotal: 127

not specifiedTotal: 80

CR2-related disorderTotal: 53

Systemic lupus erythematosus, susceptibility to, 9Total: 20

Immunodeficiency, common variable, 2Total: 9

Joubert syndrome 17Total: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001006658.3. 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			4 clinvar	203 clinvar	4 clinvar	211
missense		3 clinvar	406 clinvar	36 clinvar	1 clinvar	446
nonsense	19 clinvar	12 clinvar				31
start loss						0
frameshift	17 clinvar	9 clinvar	2 clinvar			28
splice donor/acceptor (+/-2bp)	2 clinvar	9 clinvar				11
Total	38	33	412	239	5	727

Highest pathogenic variant AF is 0.00088153355

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 17 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001006658.3	RefSeq	NP_001006659.1	19	MANE Select
ENST00000367057.8	Ensembl	ENSP00000356024.3	19	MANE Select
NM_001877.5	RefSeq	NP_001868.2	18	Standard
ENST00000367058.7	Ensembl	ENSP00000356025.3	18	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Complement and coagulation cascades - Homo sapiens (human)
B cell receptor signaling pathway - Homo sapiens (human)
Hematopoietic cell lineage - Homo sapiens (human)
Epstein-Barr virus infection - Homo sapiens (human)
B Cell Receptor Signaling Pathway

Biological Process

complement receptor mediated signaling pathway
immune response
complement activation, classical pathway
B cell differentiation
regulation of complement activation

Molecular Function

virus receptor activity
complement binding
DNA binding
complement receptor activity
transmembrane signaling receptor activity

Cellular Component

plasma membrane
integral component of membrane
receptor complex
extracellular exosome

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000367057
Coding exons: 19
Length: 35666
Individuals with no LoFs: 125652
Homozygous LoFs: 0
Heterozygous LoFs: 94
Defined: 125746
p: 0.000374

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.793	542	597	0.909	0.0000315	7113
Missense (PolyPhen)		155	192.61	0.80474		2351
Synonymous	-0.549	221	211	1.05	0.0000112	2151
Loss of Function	2.29	38	56.6	0.671	0.00000334	660

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00031	0.00031	rare
Latino/Admixed American	0.00020	0.00020	rare
Ashkenazi Jewish	0.00010	0.000099	rare
East Asian	0.0014	0.0014	notable
Finnish	0	0.0	absent
European (Non-Finnish)	0.00041	0.00040	rare
South Asian	0.00023	0.00023	rare
Other	0.00033	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Receptor for complement C3Dd, for the Epstein-Barr virus on human B-cells and T-cells and for HNRNPU (PubMed:7753047). Participates in B lymphocytes activation (PubMed:7753047). {ECO:0000269|PubMed:7753047}.;
Disease: DISEASE: Immunodeficiency, common variable, 7 (CVID7) [MIM:614699]: A primary immunodeficiency characterized by antibody deficiency, hypogammaglobulinemia, recurrent bacterial infections and an inability to mount an antibody response to antigen. The defect results from a failure of B-cell differentiation and impaired secretion of immunoglobulins; the numbers of circulating B-cells is usually in the normal range, but can be low. {ECO:0000269|PubMed:22035880}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.458

Intolerance Scores

LoFtool: 0.952
RVIS EVS: 0.06
RVIS percentile EVS: 57.56

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.558

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	High	High	High
Primary Immunodeficiency	High	High	High
Cancer	High	High	High