BTK
Bruton tyrosine kinase, the group of SH2 domain containing|Pleckstrin homology domain containing|Tec family tyrosine kinases
Basic information
Region (hg38): X:101349338-101390796
Previous symbols: [ "AGMX1", "IMD1" ]
Links
Phenotypes
GenCC
Source:
- Bruton-type agammaglobulinemia (Definitive), mode of inheritance: XL
- Bruton-type agammaglobulinemia (Supportive), mode of inheritance: XL
- short stature due to isolated growth hormone deficiency with X-linked hypogammaglobulinemia (Supportive), mode of inheritance: XL
- isolated growth hormone deficiency type III (Strong), mode of inheritance: XL
- isolated growth hormone deficiency type III (Disputed Evidence), mode of inheritance: XL
- Bruton-type agammaglobulinemia (Definitive), mode of inheritance: XL
Clinical Genomic Database
Source:
| Condition | Inheritance | Intervention Categories | Intervention/Rationale | Manifestation Categories | References |
|---|---|---|---|---|---|
| Isolated growth hormone deficiency, type III with agammaglobulinemia; Agammaglobulinemia, X-linked 1 | XL | Allergy/Immunology/Infectious; Endocrine | Antiinfectious prophylaxis, including gammaglobulins, sometimes with prophylactic antibiotics and early and aggressive treatment of infections may be beneficial; Live viral vaccines should be avoided; Recognition and treatment of growth hormone deficiency may be beneficial | Allergy/Immunology/Infectious; Endocrine | 13380950; 4578158; 3488506; 6783908; 8380905; 8013627; 7722175; 8982147; 9545398; 11445810; 12378199; 12217331; 12958074; 16159644; 16297664; 16377251; 19302039; 19651503; 18241230; 20301626 |
ClinVar
This is a list of variants' phenotypes submitted to
- X-linked agammaglobulinemia with growth hormone deficiency (123 variants)
- X-linked agammaglobulinemia (36 variants)
- not provided (31 variants)
- Autosomal recessive agammaglobulinemia 1 (6 variants)
- not specified (2 variants)
- X-linked agammaglobulinemia with growth hormone deficiency;X-linked agammaglobulinemia (1 variants)
- Inherited Immunodeficiency Diseases (1 variants)
Variants pathogenicity by type
Statistics on ClinVar variants can assist in determining whether a specific variant type in the BTK gene is commonly pathogenic or not.
In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.
Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.
| Variant type | Pathogenic | Likely pathogenic | VUS | Likely benign | Benign | Sum |
|---|---|---|---|---|---|---|
| synonymous | 75 | 10 | 85 | |||
| missense | 32 | 45 | 113 | 203 | ||
| nonsense | 49 | 57 | ||||
| start loss | 2 | |||||
| frameshift | 45 | 54 | ||||
| inframe indel | 5 | |||||
| splice donor/acceptor (+/-2bp) | 26 | 15 | 46 | |||
| splice region | 1 | 5 | 14 | 29 | 7 | 56 |
| non coding | 65 | 43 | 117 | |||
| Total | 155 | 83 | 125 | 148 | 58 |
Variants in BTK
This is a list of pathogenic ClinVar variants found in the BTK region.
You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.
| Position | Type | Phenotype | Significance | ClinVar |
|---|---|---|---|---|
| X-101349495-C-T | X-linked agammaglobulinemia with growth hormone deficiency • X-linked agammaglobulinemia | Uncertain significance (Jan 12, 2018) | ||
| X-101349541-CCA-C | Isolated congenital growth hormone deficiency • X-linked agammaglobulinemia | Likely benign (Jun 14, 2016) | ||
| X-101349543-A-C | X-linked agammaglobulinemia with growth hormone deficiency • X-linked agammaglobulinemia | Uncertain significance (Jan 13, 2018) | ||
| X-101349551-A-C | X-linked agammaglobulinemia • X-linked agammaglobulinemia with growth hormone deficiency | Benign (Apr 27, 2017) | ||
| X-101349664-C-A | X-linked agammaglobulinemia with growth hormone deficiency • X-linked agammaglobulinemia | Benign (Jan 13, 2018) | ||
| X-101349693-C-T | X-linked agammaglobulinemia • X-linked agammaglobulinemia with growth hormone deficiency | Benign (Apr 27, 2017) | ||
| X-101349769-T-G | X-linked agammaglobulinemia with growth hormone deficiency • X-linked agammaglobulinemia | Benign (Jul 14, 2021) | ||
| X-101349783-AG-A | Uncertain significance (Aug 11, 2016) | |||
| X-101349874-TATTGGCGAGCTCAGG-T | X-linked agammaglobulinemia with growth hormone deficiency | Uncertain significance (Mar 17, 2023) | ||
| X-101349887-A-C | Likely pathogenic (Jul 20, 2015) | |||
| X-101349888-G-A | X-linked agammaglobulinemia • X-linked agammaglobulinemia with growth hormone deficiency | Conflicting classifications of pathogenicity (Dec 14, 2023) | ||
| X-101349910-A-G | X-linked agammaglobulinemia | Pathogenic (Oct 01, 1994) | ||
| X-101349918-GC-G | Autosomal recessive agammaglobulinemia 1 | Pathogenic (Mar 23, 2016) | ||
| X-101349926-G-GA | Likely pathogenic (May 21, 2021) | |||
| X-101349933-G-C | X-linked agammaglobulinemia with growth hormone deficiency | Likely pathogenic (Oct 24, 2022) | ||
| X-101349934-A-G | X-linked agammaglobulinemia with growth hormone deficiency | Pathogenic (Oct 13, 2023) | ||
| X-101349938-TG-T | X-linked agammaglobulinemia with growth hormone deficiency | Pathogenic (Oct 26, 2022) | ||
| X-101349940-G-A | X-linked agammaglobulinemia | Likely pathogenic (Sep 25, 2024) | ||
| X-101349943-C-G | X-linked agammaglobulinemia • X-linked agammaglobulinemia with growth hormone deficiency | Conflicting classifications of pathogenicity (Nov 29, 2023) | ||
| X-101349943-C-T | X-linked agammaglobulinemia with growth hormone deficiency | Pathogenic (Feb 03, 2022) | ||
| X-101349944-G-A | X-linked agammaglobulinemia with growth hormone deficiency | Pathogenic (Aug 28, 2023) | ||
| X-101349957-C-T | X-linked agammaglobulinemia with growth hormone deficiency | Uncertain significance (Sep 18, 2022) | ||
| X-101349963-C-T | X-linked agammaglobulinemia with growth hormone deficiency | Likely benign (Jun 23, 2023) | ||
| X-101349965-A-G | not specified • X-linked agammaglobulinemia with growth hormone deficiency • X-linked agammaglobulinemia | Conflicting classifications of pathogenicity (Jan 25, 2024) | ||
| X-101349973-A-C | X-linked agammaglobulinemia with growth hormone deficiency | Likely benign (Jul 16, 2023) |
GnomAD
Source:
| Gene | Type | Bio Type | Transcript | Coding Exons | Length |
|---|---|---|---|---|---|
| BTK | protein_coding | protein_coding | ENST00000308731 | 18 | 36749 |
| pLI Probability LOF Intolerant | pRec Probability LOF Recessive | Individuals with no LOFs | Individuals with Homozygous LOFs | Individuals with Heterozygous LOFs | Defined | p |
|---|---|---|---|---|---|---|
| 1.00 | 0.0000351 | 0 | 0 | 0 | 0 | 0.00 |
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible in Transcript | |
|---|---|---|---|---|---|---|
| Missense | 4.04 | 72 | 253 | 0.285 | 0.0000198 | 4359 |
| Missense in Polyphen | 11 | 99.524 | 0.11053 | 1683 | ||
| Synonymous | 1.34 | 72 | 87.9 | 0.819 | 0.00000660 | 1186 |
| Loss of Function | 4.99 | 0 | 29.0 | 0.00 | 0.00000211 | 499 |
LoF frequencies by population
| Ethnicity | Sum of pLOFs | p |
|---|---|---|
| African & African-American | 0.00 | 0.00 |
| Ashkenazi Jewish | 0.00 | 0.00 |
| East Asian | 0.00 | 0.00 |
| Finnish | 0.00 | 0.00 |
| European (Non-Finnish) | 0.00 | 0.00 |
| Middle Eastern | 0.00 | 0.00 |
| South Asian | 0.00 | 0.00 |
| Other | 0.00 | 0.00 |
dbNSFP
Source:
- Function
- FUNCTION: Non-receptor tyrosine kinase indispensable for B lymphocyte development, differentiation and signaling. Binding of antigen to the B-cell antigen receptor (BCR) triggers signaling that ultimately leads to B-cell activation. After BCR engagement and activation at the plasma membrane, phosphorylates PLCG2 at several sites, igniting the downstream signaling pathway through calcium mobilization, followed by activation of the protein kinase C (PKC) family members. PLCG2 phosphorylation is performed in close cooperation with the adapter protein B-cell linker protein BLNK. BTK acts as a platform to bring together a diverse array of signaling proteins and is implicated in cytokine receptor signaling pathways. Plays an important role in the function of immune cells of innate as well as adaptive immunity, as a component of the Toll-like receptors (TLR) pathway. The TLR pathway acts as a primary surveillance system for the detection of pathogens and are crucial to the activation of host defense. Especially, is a critical molecule in regulating TLR9 activation in splenic B-cells. Within the TLR pathway, induces tyrosine phosphorylation of TIRAP which leads to TIRAP degradation. BTK plays also a critical role in transcription regulation. Induces the activity of NF-kappa-B, which is involved in regulating the expression of hundreds of genes. BTK is involved on the signaling pathway linking TLR8 and TLR9 to NF-kappa-B. Transiently phosphorylates transcription factor GTF2I on tyrosine residues in response to BCR. GTF2I then translocates to the nucleus to bind regulatory enhancer elements to modulate gene expression. ARID3A and NFAT are other transcriptional target of BTK. BTK is required for the formation of functional ARID3A DNA-binding complexes. There is however no evidence that BTK itself binds directly to DNA. BTK has a dual role in the regulation of apoptosis. {ECO:0000269|PubMed:11606584, ECO:0000269|PubMed:16415872, ECO:0000269|PubMed:16517732, ECO:0000269|PubMed:16738337, ECO:0000269|PubMed:17932028, ECO:0000269|PubMed:9012831}.;
- Disease
- DISEASE: X-linked agammaglobulinemia (XLA) [MIM:300755]: Humoral immunodeficiency disease which results in developmental defects in the maturation pathway of B-cells. Affected boys have normal levels of pre-B-cells in their bone marrow but virtually no circulating mature B-lymphocytes. This results in a lack of immunoglobulins of all classes and leads to recurrent bacterial infections like otitis, conjunctivitis, dermatitis, sinusitis in the first few years of life, or even some patients present overwhelming sepsis or meningitis, resulting in death in a few hours. Treatment in most cases is by infusion of intravenous immunoglobulin. {ECO:0000269|PubMed:10220140, ECO:0000269|PubMed:10612838, ECO:0000269|PubMed:10678660, ECO:0000269|PubMed:7627183, ECO:0000269|PubMed:7633420, ECO:0000269|PubMed:7633429, ECO:0000269|PubMed:7711734, ECO:0000269|PubMed:7809124, ECO:0000269|PubMed:7849006, ECO:0000269|PubMed:7849697, ECO:0000269|PubMed:7849721, ECO:0000269|PubMed:7880320, ECO:0000269|PubMed:7897635, ECO:0000269|PubMed:8013627, ECO:0000269|PubMed:8162018, ECO:0000269|PubMed:8162056, ECO:0000269|PubMed:8594569, ECO:0000269|PubMed:8634718, ECO:0000269|PubMed:8695804, ECO:0000269|PubMed:8723128, ECO:0000269|PubMed:8834236, ECO:0000269|PubMed:9016530, ECO:0000269|PubMed:9260159, ECO:0000269|PubMed:9280283, ECO:0000269|PubMed:9445504, ECO:0000269|PubMed:9545398}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: X-linked hypogammaglobulinemia and isolated growth hormone deficiency (XLA-IGHD) [MIM:307200]: In rare cases XLA is inherited together with isolated growth hormone deficiency (IGHD). {ECO:0000269|PubMed:8013627}. Note=The disease may be caused by mutations affecting the gene represented in this entry.;
- Pathway
- Primary immunodeficiency - Homo sapiens (human);Platelet activation - Homo sapiens (human);B cell receptor signaling pathway - Homo sapiens (human);Fc epsilon RI signaling pathway - Homo sapiens (human);Osteoclast differentiation - Homo sapiens (human);NF-kappa B signaling pathway - Homo sapiens (human);Fc Epsilon Receptor I Signaling in Mast Cells;IL-5 Signaling Pathway;Regulation of toll-like receptor signaling pathway;Thymic Stromal LymphoPoietin (TSLP) Signaling Pathway;B Cell Receptor Signaling Pathway;Kit receptor signaling pathway;Antigen activates B Cell Receptor (BCR) leading to generation of second messengers;Signal Transduction;DAP12 signaling;DAP12 interactions;phosphoinositides and their downstream targets;bcr signaling pathway;Toll-Like Receptors Cascades;Signaling by the B Cell Receptor (BCR);Fcgamma receptor (FCGR) dependent phagocytosis;FCERI mediated Ca+2 mobilization;Fc epsilon receptor (FCERI) signaling;Innate Immune System;Immune System;RHO GTPases Activate WASPs and WAVEs;Adaptive Immune System;BCR;Antigen processing-Cross presentation;Class I MHC mediated antigen processing & presentation;IL-7 signaling;RHO GTPase Effectors;Signaling by Rho GTPases;fc epsilon receptor i signaling in mast cells;BCR signaling pathway;JAK STAT pathway and regulation;Regulation of actin dynamics for phagocytic cup formation;EPO signaling;Class I PI3K signaling events;EPO signaling pathway;ER-Phagosome pathway;IL6;Toll Like Receptor 4 (TLR4) Cascade;VEGF;MyD88:Mal cascade initiated on plasma membrane;Toll Like Receptor TLR1:TLR2 Cascade;Toll Like Receptor TLR6:TLR2 Cascade;Toll Like Receptor 2 (TLR2) Cascade;Fc-epsilon receptor I signaling in mast cells;FAS (CD95) signaling pathway
(Consensus)
Recessive Scores
- pRec
- 0.560
Intolerance Scores
- loftool
- rvis_EVS
- -0.12
- rvis_percentile_EVS
- 44.89
Haploinsufficiency Scores
- pHI
- 0.579
- hipred
- Y
- hipred_score
- 0.704
- ghis
- 0.545
Essentials
- essential_gene_CRISPR
- N
- essential_gene_CRISPR2
- N
- essential_gene_gene_trap
- N
- gene_indispensability_pred
- E
- gene_indispensability_score
- 0.986
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |
Mouse Genome Informatics
- Gene name
- Btk
- Phenotype
- integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); growth/size/body region phenotype; cellular phenotype; homeostasis/metabolism phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); hematopoietic system phenotype; neoplasm; limbs/digits/tail phenotype; digestive/alimentary phenotype; immune system phenotype;
Zebrafish Information Network
- Gene name
- btk
- Affected structure
- whole organism
- Phenotype tag
- abnormal
- Phenotype quality
- wholly dorsalized
Gene ontology
- Biological process
- positive regulation of type III hypersensitivity;positive regulation of type I hypersensitivity;negative regulation of cytokine production;adaptive immune response;B cell affinity maturation;histamine secretion by mast cell;regulation of B cell cytokine production;MyD88-dependent toll-like receptor signaling pathway;regulation of B cell apoptotic process;protein phosphorylation;I-kappaB kinase/NF-kappaB signaling;mesoderm development;peptidyl-tyrosine phosphorylation;calcium-mediated signaling;negative regulation of B cell proliferation;cellular response to reactive oxygen species;intracellular signal transduction;peptidyl-tyrosine autophosphorylation;Fc-epsilon receptor signaling pathway;B cell activation;innate immune response;positive regulation of B cell differentiation;cell maturation;T cell receptor signaling pathway;B cell receptor signaling pathway;positive regulation of NF-kappaB transcription factor activity;cellular response to molecule of fungal origin;apoptotic signaling pathway;cellular response to interleukin-7
- Cellular component
- nucleus;cytoplasm;cytosol;plasma membrane;cytoplasmic vesicle;mast cell granule;membrane raft;perinuclear region of cytoplasm
- Molecular function
- protein tyrosine kinase activity;non-membrane spanning protein tyrosine kinase activity;protein binding;ATP binding;phosphatidylinositol-3,4,5-trisphosphate binding;identical protein binding;metal ion binding