JAK2
Janus kinase 2, the group of FERM domain containing|Jak family tyrosine kinases|SH2 domain containing
Basic information
Region (hg38): 9:4984389-5129948
Links
Phenotypes
GenCC
Source:
- thrombocythemia 3 (Strong), mode of inheritance: AD
- familial thrombocytosis (Supportive), mode of inheritance: AD
- thrombocythemia 3 (Strong), mode of inheritance: AD
Clinical Genomic Database
Source:
| Condition | Inheritance | Intervention Categories | Intervention/Rationale | Manifestation Categories | References |
|---|---|---|---|---|---|
| Thrombocythemia 3 | AD | Hematologic | Individuals may be at high risk of thrombosis, and preventive measures and early treatment of manifestations may be beneficial | Hematologic | 16762626; 16707754; 17989398; 19036091; 19287384; 19287385; 19338077; 19847199; 22397670; 22696908; 22571758 |
ClinVar
This is a list of variants' phenotypes submitted to
- not provided (183 variants)
- not specified (34 variants)
- Inborn genetic diseases (23 variants)
- JAK2-related condition (13 variants)
- Thrombocythemia 3 (11 variants)
- Budd-Chiari syndrome (8 variants)
- 6 conditions (4 variants)
- Acquired polycythemia vera (3 variants)
- Myeloproliferative disorder (2 variants)
- Subacute lymphoid leukemia (1 variants)
- Splenomegaly;Primary myelofibrosis (1 variants)
- Primary myelofibrosis (1 variants)
- Premature ovarian failure (1 variants)
- Primary familial polycythemia due to EPO receptor mutation (1 variants)
- Budd-Chiari syndrome, susceptibility to, somatic (1 variants)
- See cases (1 variants)
- Hereditary breast ovarian cancer syndrome (1 variants)
- Thrombocythemia 3;Acquired polycythemia vera;Acute myeloid leukemia (1 variants)
- Polycythemia (1 variants)
- Chronic myelogenous leukemia, BCR-ABL1 positive (1 variants)
- Acute myeloid leukemia (1 variants)
Variants pathogenicity by type
Statistics on ClinVar variants can assist in determining whether a specific variant type in the JAK2 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 | 29 | 14 | 46 | |||
| missense | 80 | 11 | 95 | |||
| nonsense | 2 | |||||
| start loss | 0 | |||||
| frameshift | 4 | |||||
| inframe indel | 2 | |||||
| splice donor/acceptor (+/-2bp) | 3 | |||||
| splice region ? | 5 | 9 | 2 | 16 | ||
| non coding ? | 18 | 34 | 60 | |||
| Total | 0 | 4 | 101 | 58 | 49 |
Highest pathogenic variant AF is 0.0000394
Variants in JAK2
This is a list of pathogenic ClinVar variants found in the JAK2 region.
You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.
| Position | Type | Phenotype | Significance | ClinVar |
|---|---|---|---|---|
| 9-4985601-C-T | Budd-Chiari syndrome | Uncertain significance (Jun 14, 2016) | ||
| 9-5021738-G-A | Benign (Nov 12, 2018) | |||
| 9-5022025-G-T | Likely benign (Mar 17, 2023) | |||
| 9-5022042-A-G | Uncertain significance (Nov 22, 2023) | |||
| 9-5022073-C-T | Uncertain significance (Aug 16, 2023) | |||
| 9-5022081-A-G | Thrombocythemia 3 | Uncertain significance (-) | ||
| 9-5022091-T-C | Uncertain significance (Dec 11, 2023) | |||
| 9-5022124-C-A | Inborn genetic diseases | Conflicting classifications of pathogenicity (Jan 09, 2024) | ||
| 9-5022128-T-G | Likely benign (Feb 26, 2023) | |||
| 9-5022130-G-A | not specified | Conflicting classifications of pathogenicity (Nov 01, 2023) | ||
| 9-5022163-C-G | not specified | Uncertain significance (Mar 19, 2021) | ||
| 9-5022163-C-T | Inborn genetic diseases | Uncertain significance (Aug 21, 2023) | ||
| 9-5022168-G-A | Uncertain significance (May 12, 2022) | |||
| 9-5022175-T-C | Uncertain significance (Jul 29, 2023) | |||
| 9-5022213-G-T | Uncertain significance (Jul 29, 2023) | |||
| 9-5022214-G-T | See cases | Likely pathogenic (Apr 18, 2023) | ||
| 9-5022218-G-A | Uncertain significance (Jan 09, 2024) | |||
| 9-5029779-C-G | Likely benign (Oct 13, 2023) | |||
| 9-5029785-A-G | Uncertain significance (Aug 17, 2023) | |||
| 9-5029804-A-C | Uncertain significance (Jun 16, 2023) | |||
| 9-5029845-C-G | Inborn genetic diseases | Uncertain significance (May 25, 2022) | ||
| 9-5029858-T-C | Uncertain significance (Mar 02, 2023) | |||
| 9-5029878-A-G | Uncertain significance (Feb 01, 2023) | |||
| 9-5029884-C-T | Uncertain significance (Oct 03, 2022) | |||
| 9-5029893-C-G | Likely benign (Jan 02, 2024) |
GnomAD
Source:
| Gene | Type | Bio Type | Transcript | Coding Exons | Length |
|---|---|---|---|---|---|
| JAK2 | protein_coding | protein_coding | ENST00000381652 | 23 | 143151 |
| pLI Probability LOF Intolerant | pRec Probability LOF Recessive | Individuals with no LOFs | Individuals with Homozygous LOFs | Individuals with Heterozygous LOFs | Defined | p |
|---|---|---|---|---|---|---|
| 0.654 | 0.346 | 125717 | 0 | 29 | 125746 | 0.000115 |
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible in Transcript | |
|---|---|---|---|---|---|---|
| Missense | 0.896 | 518 | 579 | 0.895 | 0.0000288 | 7523 |
| Missense in Polyphen | 146 | 215.62 | 0.6771 | 2887 | ||
| Synonymous | -1.21 | 210 | 189 | 1.11 | 0.00000916 | 1997 |
| Loss of Function | 5.66 | 13 | 60.6 | 0.215 | 0.00000337 | 763 |
LoF frequencies by population
| Ethnicity | Sum of pLOFs | p |
|---|---|---|
| African & African-American | 0.000192 | 0.000192 |
| Ashkenazi Jewish | 0.000100 | 0.0000992 |
| East Asian | 0.000283 | 0.000272 |
| Finnish | 0.00 | 0.00 |
| European (Non-Finnish) | 0.000136 | 0.000132 |
| Middle Eastern | 0.000283 | 0.000272 |
| South Asian | 0.0000327 | 0.0000327 |
| Other | 0.000163 | 0.000163 |
dbNSFP
Source:
- Function
- FUNCTION: Non-receptor tyrosine kinase involved in various processes such as cell growth, development, differentiation or histone modifications. Mediates essential signaling events in both innate and adaptive immunity. In the cytoplasm, plays a pivotal role in signal transduction via its association with type I receptors such as growth hormone (GHR), prolactin (PRLR), leptin (LEPR), erythropoietin (EPOR), thrombopoietin (THPO); or type II receptors including IFN-alpha, IFN-beta, IFN-gamma and multiple interleukins (PubMed:7615558). Following ligand-binding to cell surface receptors, phosphorylates specific tyrosine residues on the cytoplasmic tails of the receptor, creating docking sites for STATs proteins (PubMed:9618263). Subsequently, phosphorylates the STATs proteins once they are recruited to the receptor. Phosphorylated STATs then form homodimer or heterodimers and translocate to the nucleus to activate gene transcription. For example, cell stimulation with erythropoietin (EPO) during erythropoiesis leads to JAK2 autophosphorylation, activation, and its association with erythropoietin receptor (EPOR) that becomes phosphorylated in its cytoplasmic domain. Then, STAT5 (STAT5A or STAT5B) is recruited, phosphorylated and activated by JAK2. Once activated, dimerized STAT5 translocates into the nucleus and promotes the transcription of several essential genes involved in the modulation of erythropoiesis. Part of a signaling cascade that is activated by increased cellular retinol and that leads to the activation of STAT5 (STAT5A or STAT5B) (PubMed:21368206). In addition, JAK2 mediates angiotensin-2-induced ARHGEF1 phosphorylation (PubMed:20098430). Plays a role in cell cycle by phosphorylating CDKN1B (PubMed:21423214). Cooperates with TEC through reciprocal phosphorylation to mediate cytokine-driven activation of FOS transcription. In the nucleus, plays a key role in chromatin by specifically mediating phosphorylation of 'Tyr-41' of histone H3 (H3Y41ph), a specific tag that promotes exclusion of CBX5 (HP1 alpha) from chromatin (PubMed:19783980). {ECO:0000269|PubMed:12023369, ECO:0000269|PubMed:19783980, ECO:0000269|PubMed:20098430, ECO:0000269|PubMed:21368206, ECO:0000269|PubMed:21423214, ECO:0000269|PubMed:7615558, ECO:0000269|PubMed:9618263}.;
- Disease
- DISEASE: Note=Chromosomal aberrations involving JAK2 are found in both chronic and acute forms of eosinophilic, lymphoblastic and myeloid leukemia. Translocation t(8;9)(p22;p24) with PCM1 links the protein kinase domain of JAK2 to the major portion of PCM1. Translocation t(9;12)(p24;p13) with ETV6.; DISEASE: Budd-Chiari syndrome (BDCHS) [MIM:600880]: A syndrome caused by obstruction of hepatic venous outflow involving either the hepatic veins or the terminal segment of the inferior vena cava. Obstructions are generally caused by thrombosis and lead to hepatic congestion and ischemic necrosis. Clinical manifestations observed in the majority of patients include hepatomegaly, right upper quadrant pain and abdominal ascites. Budd-Chiari syndrome is associated with a combination of disease states including primary myeloproliferative syndromes and thrombophilia due to factor V Leiden, protein C deficiency and antithrombin III deficiency. Budd-Chiari syndrome is a rare but typical complication in patients with polycythemia vera. {ECO:0000269|PubMed:16707754}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.; DISEASE: Polycythemia vera (PV) [MIM:263300]: A myeloproliferative disorder characterized by abnormal proliferation of all hematopoietic bone marrow elements, erythroid hyperplasia, an absolute increase in total blood volume, but also by myeloid leukocytosis, thrombocytosis and splenomegaly. {ECO:0000269|PubMed:15781101, ECO:0000269|PubMed:15793561, ECO:0000269|PubMed:15858187, ECO:0000269|PubMed:16603627}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Thrombocythemia 3 (THCYT3) [MIM:614521]: A myeloproliferative disorder characterized by excessive platelet production, resulting in increased numbers of circulating platelets. It can be associated with spontaneous hemorrhages and thrombotic episodes. {ECO:0000269|PubMed:16325696, ECO:0000269|PubMed:22397670}. Note=The disease may be caused by mutations affecting the gene represented in this entry.; DISEASE: Myelofibrosis (MYELOF) [MIM:254450]: A disorder characterized by replacement of the bone marrow by fibrous tissue, occurring in association with a myeloproliferative disorder. Clinical manifestations may include anemia, pallor, splenomegaly, hypermetabolic state, petechiae, ecchymosis, bleeding, lymphadenopathy, hepatomegaly, portal hypertension. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Leukemia, acute myelogenous (AML) [MIM:601626]: A subtype of acute leukemia, a cancer of the white blood cells. AML is a malignant disease of bone marrow characterized by maturational arrest of hematopoietic precursors at an early stage of development. Clonal expansion of myeloid blasts occurs in bone marrow, blood, and other tissue. Myelogenous leukemias develop from changes in cells that normally produce neutrophils, basophils, eosinophils and monocytes. {ECO:0000269|PubMed:16247455}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
- Pathway
- PI3K-Akt signaling pathway - Homo sapiens (human);Adipocytokine signaling pathway - Homo sapiens (human);Kaposi,s sarcoma-associated herpesvirus infection - Homo sapiens (human);AGE-RAGE signaling pathway in diabetic complications - Homo sapiens (human);Jak-STAT signaling pathway - Homo sapiens (human);Influenza A - Homo sapiens (human);Chemokine signaling pathway - Homo sapiens (human);Signaling pathways regulating pluripotency of stem cells - Homo sapiens (human);Necroptosis - Homo sapiens (human);Tuberculosis - Homo sapiens (human);Th17 cell differentiation - Homo sapiens (human);Th1 and Th2 cell differentiation - Homo sapiens (human);Leishmaniasis - Homo sapiens (human);Toxoplasmosis - Homo sapiens (human);Prolactin signaling pathway - Homo sapiens (human);Pathways in cancer - Homo sapiens (human);Measles - Homo sapiens (human);Cholinergic synapse - Homo sapiens (human);Herpes simplex infection - Homo sapiens (human);JAK-STAT-Core;IL-5 Signaling Pathway;Leptin signaling pathway;Human Thyroid Stimulating Hormone (TSH) signaling pathway;Prolactin Signaling Pathway;IL17 signaling pathway;Thymic Stromal LymphoPoietin (TSLP) Signaling Pathway;AGE-RAGE pathway;Interleukin-11 Signaling Pathway;Oncostatin M Signaling Pathway;Brain-Derived Neurotrophic Factor (BDNF) signaling pathway;Integrated Lung Cancer Pathway;JAK-STAT;Mesodermal Commitment Pathway;IL-3 Signaling Pathway;Kit receptor signaling pathway;IL-6 signaling pathway;IL-4 Signaling Pathway;Chemokine signaling pathway;Focal Adhesion-PI3K-Akt-mTOR-signaling pathway;Leptin Insulin Overlap;PDGFR-beta pathway;PI3K-Akt Signaling Pathway;The human immune response to tuberculosis;EGF-EGFR Signaling Pathway;no2-dependent il-12 pathway in nk cells;EPO Receptor Signaling;Notch Signaling Pathway;Type II interferon signaling (IFNG);Serotonin Receptor 2 and STAT3 Signaling;Signaling by GPCR;Interleukin-4 and 13 signaling;RAF activation;Notch;Interleukin-12 family signaling;Disease;IL-3 signaling;Signal Transduction;Signaling by Interleukins;inhibition of cellular proliferation by gleevec;bioactive peptide induced signaling pathway;il12 and stat4 dependent signaling pathway in th1 development;IL-6-type cytokine receptor ligand interactions;chaperones modulate interferon signaling pathway;erythropoietin mediated neuroprotection through nf-kb;stat3 signaling pathway;ifn gamma signaling pathway;Growth hormone receptor signaling;il 6 signaling pathway;Prolactin receptor signaling;role of erbb2 in signal transduction and oncology;Prolactin;Cytokine Signaling in Immune system;JAK STAT MolecularVariation 1;IL-12 signaling;Factors involved in megakaryocyte development and platelet production;Growth hormone signaling;Regulation of IFNG signaling;il 3 signaling pathway;RMTs methylate histone arginines;Chromatin modifying enzymes;Oncostatin_M;Immune System;Interleukin receptor SHC signaling;Interleukin-2 family signaling;Cyclin D associated events in G1;G1 Phase;IL5-mediated signaling events;IFN gamma signaling;KitReceptor;Mitotic G1-G1/S phases;ErbB4 signaling events;IL-23 signaling;epo signaling pathway;MAPK1 (ERK2) activation;IL-5 signaling;IL-6 signaling;RAF-independent MAPK1/3 activation;IL-7 signaling;Interleukin-23 signaling;tpo signaling pathway;EGFR1;SHP2 signaling;growth hormone signaling pathway;CXCR4-mediated signaling events;JAK STAT MolecularVariation 2;Hemostasis;RAF/MAP kinase cascade;MAPK1/MAPK3 signaling;MAPK family signaling cascades;JAK STAT pathway and regulation;LIF signaling;Signaling by Leptin;IL11;EPO signaling;Chromatin organization;IL3;Gastrin;Interferon gamma signaling;IFN-gamma pathway;IL4;EPO signaling pathway;Signaling by SCF-KIT;IL5;Leptin;Interleukin-27 signaling;Cell Cycle;IL6;Interleukin-12 signaling;Signaling by Receptor Tyrosine Kinases;TPO signaling;MAPK3 (ERK1) activation;Signaling by RAS mutants;VEGF;Cell Cycle, Mitotic;G beta:gamma signalling through PI3Kgamma;G-protein beta:gamma signalling;GPCR downstream signalling;Signaling by moderate kinase activity BRAF mutants;Paradoxical activation of RAF signaling by kinase inactive BRAF;ErbB2/ErbB3 signaling events;Notch-mediated HES/HEY network;IL23-mediated signaling events;GMCSF-mediated signaling events;IL27-mediated signaling events;Signaling by BRAF and RAF fusions;Oncogenic MAPK signaling;Diseases of signal transduction;Interferon Signaling;S1P3 pathway;Signaling events mediated by Stem cell factor receptor (c-Kit);PDGFR-beta signaling pathway;IL4-mediated signaling events;Signaling events mediated by PTP1B;Interleukin-6 signaling;Interleukin-6 family signaling;IL6-mediated signaling events;Endothelins;IL3-mediated signaling events;IL12-mediated signaling events;TSLP;Interleukin-3, 5 and GM-CSF signaling
(Consensus)
Recessive Scores
- pRec
- 0.934
Intolerance Scores
- loftool
- 0.189
- rvis_EVS
- -0.37
- rvis_percentile_EVS
- 28.22
Haploinsufficiency Scores
- pHI
- 0.939
- hipred
- Y
- hipred_score
- 0.756
- ghis
- 0.537
Essentials
- essential_gene_CRISPR
- N
- essential_gene_CRISPR2
- N
- essential_gene_gene_trap
- N
- gene_indispensability_pred
- E
- gene_indispensability_score
- 0.991
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |
Mouse Genome Informatics
- Gene name
- Jak2
- Phenotype
- neoplasm; reproductive system phenotype; normal 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; liver/biliary system phenotype; embryo phenotype; skeleton phenotype; immune system phenotype; endocrine/exocrine gland 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;
Zebrafish Information Network
- Gene name
- jak2a
- Affected structure
- nucleate erythrocyte
- Phenotype tag
- abnormal
- Phenotype quality
- decreased amount
Gene ontology
- Biological process
- MAPK cascade;activation of MAPKK activity;adaptive immune response;protein phosphorylation;apoptotic process;activation of cysteine-type endopeptidase activity involved in apoptotic process;signal transduction;enzyme linked receptor protein signaling pathway;G protein-coupled receptor signaling pathway;positive regulation of cytosolic calcium ion concentration;JAK-STAT cascade;tyrosine phosphorylation of STAT protein;mesoderm development;blood coagulation;negative regulation of cell population proliferation;intrinsic apoptotic signaling pathway in response to oxidative stress;negative regulation of cardiac muscle cell apoptotic process;positive regulation of cell-substrate adhesion;positive regulation of phosphatidylinositol 3-kinase signaling;peptidyl-tyrosine phosphorylation;cytokine-mediated signaling pathway;negative regulation of cell-cell adhesion;actin filament polymerization;cell differentiation;erythrocyte differentiation;positive regulation of cell migration;axon regeneration;mineralocorticoid receptor signaling pathway;positive regulation of insulin secretion;response to lipopolysaccharide;positive regulation of phosphoprotein phosphatase activity;positive regulation of interleukin-1 beta production;positive regulation of tumor necrosis factor production;obsolete positive regulation of protein import into nucleus, translocation;response to hydroperoxide;tumor necrosis factor-mediated signaling pathway;response to tumor necrosis factor;histone H3-Y41 phosphorylation;intracellular signal transduction;interleukin-12-mediated signaling pathway;interleukin-23-mediated signaling pathway;positive regulation of tyrosine phosphorylation of STAT protein;activation of Janus kinase activity;positive regulation of DNA binding;negative regulation of DNA binding;negative regulation of neuron apoptotic process;regulation of nitric oxide biosynthetic process;positive regulation of nitric oxide biosynthetic process;positive regulation of cell differentiation;negative regulation of heart contraction;regulation of JAK-STAT cascade;positive regulation of Ras protein signal transduction;response to antibiotic;protein autophosphorylation;platelet-derived growth factor receptor signaling pathway;regulation of inflammatory response;positive regulation of inflammatory response;positive regulation of peptidyl-tyrosine phosphorylation;modulation of chemical synaptic transmission;positive regulation of cell activation;positive regulation of DNA-binding transcription factor activity;positive regulation of nitric-oxide synthase biosynthetic process;interferon-gamma-mediated signaling pathway;regulation of interferon-gamma-mediated signaling pathway;growth hormone receptor signaling pathway;JAK-STAT cascade involved in growth hormone signaling pathway;positive regulation of growth hormone receptor signaling pathway;mammary gland epithelium development;interleukin-6-mediated signaling pathway;interleukin-27-mediated signaling pathway;response to interleukin-12;interleukin-35-mediated signaling pathway;extrinsic apoptotic signaling pathway;activation of cysteine-type endopeptidase activity involved in apoptotic signaling pathway;postsynapse to nucleus signaling pathway;positive regulation of cold-induced thermogenesis;positive regulation of growth factor dependent skeletal muscle satellite cell proliferation;positive regulation of epithelial cell apoptotic process;positive regulation of vascular smooth muscle cell proliferation
- Cellular component
- nucleus;nucleoplasm;cytoplasm;cytosol;cytoskeleton;plasma membrane;caveola;focal adhesion;nuclear matrix;endosome lumen;membrane raft;postsynapse;glutamatergic synapse
- Molecular function
- protein kinase activity;protein tyrosine kinase activity;non-membrane spanning protein tyrosine kinase activity;Ras guanyl-nucleotide exchange factor activity;signaling receptor binding;growth hormone receptor binding;interleukin-12 receptor binding;protein binding;ATP binding;protein C-terminus binding;protein kinase binding;heme binding;type 1 angiotensin receptor binding;acetylcholine receptor binding;histone kinase activity (H3-Y41 specific);SH2 domain binding;histone binding;identical protein binding;phosphatidylinositol 3-kinase binding;insulin receptor substrate binding;metal ion binding;peptide hormone receptor binding