GeneBe

CD19

protein-coding

CD19 molecule, the group of CD molecules|Minor histocompatibility antigens|Immunoglobulin like domain containing

Gene summary

This gene encodes a member of the immunoglobulin gene superfamily. Expression of this cell surface protein is restricted to B cell lymphocytes. This protein is a reliable marker for pre-B cells but its expression diminishes during terminal B cell differentiation in antibody secreting plasma cells. The protein has two N-terminal extracellular Ig-like domains separated by a non-Ig-like domain, a hydrophobic transmembrane domain, and a large C-terminal cytoplasmic domain. This protein forms a complex with several membrane proteins including complement receptor type 2 (CD21) and tetraspanin (CD81) and this complex reduces the threshold for antigen-initiated B cell activation. Activation of this B-cell antigen receptor complex activates the phosphatidylinositol 3-kinase signalling pathway and the subsequent release of intracellular stores of calcium ions. This protein is a target of chimeric antigen receptor (CAR) T-cells used in the treatment of lymphoblastic leukemia. Mutations in this gene are associated with the disease common variable immunodeficiency 3 (CVID3) which results in a failure of B-cell differentiation and impaired secretion of immunoglobulins. CVID3 is characterized by hypogammaglobulinemia, an inability to mount an antibody response to antigen, and recurrent bacterial infections. Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Jul 2020]

MANE transcript

NM_001770.6

Inheritance

AR

ClinVar variants

P:17U:172B:130

Top phenotype

Immunodeficiency, common variable 3

gnomAD constraint

pLI —, LoF o/e 0.17

Max pathogenic AF

—

Genomic locus

chr16:28,931,965-28,939,342

External References & Databases

Ensembl (ENSG00000177455)NCBI Gene (930)OMIM (107265)HGNC:1633GenCCUniProt (P15391)AlphaFoldClinVar (CD19)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~7.4 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

immunodeficiency, common variable, 3DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013283

Submitter: ClinGen

*CD19* was first reported in relation to autosomal recessive immunodeficiency, common variable, 3 in 2006 (van Zelm MC, et al., 2006, PMID: 16672701). On mature B cells, CD19, CD81, CD21 and CD225 form the CD19 complex that signals in conjunction with the B cell antigen receptor (BcR), thereby decreasing the threshold for BcR-dependent signaling. Biallelic variation in this gene thus results in profound hypogammaglobulinemia due to a poor response to antigen. These patients are characterized by moderately severe hypogammaglobulinemia, impaired antibody responses on vaccination, and impaired memory B-cell formation. This gene-disease relationship is supported by both genetic and experimental evidence. At least eight variants (missense, splice site, and frameshift) have been reported in seven probands (PMIDs: 16672701, 21159371, 24684239, 34490048 and 21330302) and three additional affected family members. A role in disease is supported by the function of *CD19* in lowering the threshold for antigen receptor stimulation (PMID: 1373518), which is disrupted in patient cells (PMID: 16672701). Expression of *CD19* during B-cell differentiation provides further evidence; the surface molecule CD19 appears early and remains on the B cell until it differentiates into a plasma cell (PMID: 6408173). A CD19-/- mouse model recapitulates the profound deficiency in responding to protein antigens as well as impaired response to vaccination (PMID: 7543183) and live virus (PMID: 9653091). Recapitulation of hypogammaglobulinemia in the CD19-/- mouse can be rescued by human CD19 (PMID: 9144478). In summary *CD19* is definitively associated with autosomal recessive immunodeficiency, common variable, 3. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.

immunodeficiency, common variable, 3STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013283

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Immunodeficiency, common variable 3AR

Manifestation: Allergy/Immunology/Infectious

Intervention: Allergy/Immunology/Infectious

Rationale: Indidivuals may demonstrate increased susceptibility to infections, and antiinfectious prophylaxis and early and aggressive treatment of infections may be beneficial

Refs: 16672701Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CD19 variants in ClinVar

8 Conditions Cataloged
not providedTotal: 345
Inborn genetic diseasesTotal: 66
Immunodeficiency, common variable, 3Total: 48
not specifiedTotal: 36
CD19-related disorderTotal: 15
Inherited Immunodeficiency DiseasesTotal: 2
Immunodeficiency, common variable, 2Total: 1
Primary ciliary dyskinesiaTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001770.6. 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.

EffectPLPVUSLBBSum
synonymous
3
clinvar
117
clinvar
1
clinvar
 121
missense
1
clinvar
1
clinvar
167
clinvar
11
clinvar
 180
nonsense
1
clinvar
2
clinvar
 3
start loss
0
frameshift
5
clinvar
1
clinvar
2
clinvar
 8
splice donor/acceptor (+/-2bp)
1
clinvar
5
clinvar
1
clinvar
 7
Total891721291319

Highest pathogenic variant AF is 0.0000030979088

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 7 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_001770.6RefSeqNP_001761.314MANE Select
ENST00000538922.8EnsemblENSP00000437940.214MANE Select
NM_001178098.2RefSeqNP_001171569.114Standard
NM_001385732.1RefSeqNP_001372661.113Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • PI3K-Akt signaling pathway - Homo sapiens (human)
  • Primary immunodeficiency - Homo sapiens (human)
  • B cell receptor signaling pathway - Homo sapiens (human)
  • Hematopoietic cell lineage - Homo sapiens (human)
  • Epstein-Barr virus infection - Homo sapiens (human)

Biological Process

  • cellular defense response
  • cell surface receptor signaling pathway
  • regulation of complement activation
  • phosphatidylinositol phosphorylation
  • regulation of immune response

Molecular Function

  • protein binding
  • phosphatidylinositol-4,5-bisphosphate 3-kinase activity

Cellular Component

  • plasma membrane
  • integral component of plasma membrane
  • external side of plasma membrane
  • protein-containing complex
  • extracellular exosome

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000538922
Coding exons
14
Length
7408
Individuals with no LoFs
125742
Homozygous LoFs
0
Heterozygous LoFs
6
Defined
125748
p
0.0000239
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense1.032703220.8390.00001913571
Missense (PolyPhen)124150.040.826451639
Synonymous-0.2171381351.020.000008561137
Loss of Function4.19529.60.1690.00000134343

Population LoF Frequency

PopulationCAFp-valueStatus
African0.0000620.000062rare
Latino/Admixed American0.0000290.000029rare
Ashkenazi Jewish00.0absent
East Asian00.0absent
Finnish00.0absent
European (Non-Finnish)0.0000180.000018rare
South Asian0.0000650.000065rare
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Assembles with the antigen receptor of B-lymphocytes in order to decrease the threshold for antigen receptor-dependent stimulation.;
Disease
DISEASE: Immunodeficiency, common variable, 3 (CVID3) [MIM:613493]: 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:16672701}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.517

Intolerance Scores

LoFtool
0.411
RVIS EVS
-0.18
RVIS percentile EVS
40.36

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.674

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
Feedback | API | MCP | Annotate VCF | Sitemap | About | Privacy & Terms
For research and educational, non-commercial use only. Not for clinical or diagnostic use. GeneBe does not provide medical advice. Data use for AI modeling is prohibited: if used, the cost is $0.001 per byte of downloaded uncompressed data.