TET2

tet methylcytosine dioxygenase 2, the group of Tet methylcytosine dioxygenase family

Basic information

Region (hg38): 4:105145874-105279816

Previous symbols: [ "KIAA1546" ]

Links

ENSG00000168769 ∙ NCBI:54790 ∙ OMIM:612839 ∙ HGNC:25941 ∙ Uniprot:Q6N021 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• immunodeficiency 75 (Strong), mode of inheritance: AR
• pulmonary arterial hypertension (Moderate), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Immunodeficiency 75 with lymphoproliferation	AR	Allergy/Immunology/Infectious; Oncologic	Individuals have been described with severe and early-onset infections, and awareness may allow early and aggressive management of infections; The condition can include hematologic malignancies, and awareness may allow early diagnosis and management; HSCT has been described	Allergy/Immunology/Infectious; Neurologic; Oncologic	32518946

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the TET2 gene.

• not provided (297 variants)
• not specified (61 variants)
• Inborn genetic diseases (18 variants)
• Immunodeficiency 75 (11 variants)
• TET2-related condition (10 variants)
• Angioimmunoblastic T-cell lymphoma (2 variants)
• Myelodysplastic syndrome (2 variants)
• Squamous cell carcinoma (1 variants)
• Atypical chronic myeloid leukemia, BCR-ABL1 negative (1 variants)
• Clonal hematopoiesis (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the TET2 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			1	60	7	68
missense	1		148	8	18	175
nonsense	6	2	23			31
start loss						0
frameshift	14	3	19			36
inframe indel			5			5
splice donor/acceptor (+/-2bp)		2				2
splice region			2	3	1	6
non coding			1	7	6	14
Total	21	7	197	75	31

Highest pathogenic variant AF is 0.00000657

Variants in TET2

This is a list of pathogenic ClinVar variants found in the TET2 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
4-105233833-TATAGATAG-T		not specified	Benign (Jan 24, 2024)
4-105233951-G-A			Likely benign (Apr 24, 2023)
4-105233957-A-G			Likely benign (Jul 30, 2023)
4-105233963-C-T			Likely benign (Sep 05, 2023)
4-105233964-C-G			Likely benign (Aug 09, 2022)
4-105233978-C-T			Likely benign (Jun 15, 2018)
4-105233979-A-C			Benign/Likely benign (Jan 29, 2024)
4-105234002-A-C			Likely benign (Sep 01, 2023)
4-105234016-G-T			Uncertain significance (Dec 27, 2023)
4-105234022-C-G			Uncertain significance (Sep 15, 2022)
4-105234028-C-G		not specified	Benign (Jan 31, 2024)
4-105234037-C-T			Uncertain significance (Jan 25, 2022)
4-105234042-C-T		not specified	Benign (Jan 31, 2024)
4-105234055-G-T			Uncertain significance (Jun 02, 2022)
4-105234058-C-T			Uncertain significance (Jun 07, 2022)
4-105234113-C-T			Likely benign (Dec 09, 2023)
4-105234122-T-C			Likely benign (Jul 19, 2023)
4-105234138-A-T			Uncertain significance (Jul 16, 2023)
4-105234139-T-C		not specified	not provided (Sep 19, 2013)
4-105234182-A-G			Likely benign (Sep 13, 2023)
4-105234193-G-T			Uncertain significance (Dec 09, 2023)
4-105234204-T-C			Uncertain significance (Nov 11, 2022)
4-105234215-T-C		TET2-related disorder	Likely benign (Aug 18, 2021)
4-105234228-C-T			Uncertain significance (Feb 20, 2022)
4-105234229-G-GCA			Uncertain significance (Feb 20, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
TET2	protein_coding	protein_coding	ENST00000540549	9	133942

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
4.33e-54	3.09e-10	125608	0	139	125747	0.000553

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.62	872	1.02e+3	0.857	0.0000506	13154
Missense in Polyphen		186	266.38	0.69825		3401
Synonymous	1.49	341	378	0.902	0.0000192	3820
Loss of Function	-1.06	76	66.7	1.14	0.00000330	890

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000861	0.000861
Ashkenazi Jewish	0.00109	0.00109
East Asian	0.000436	0.000435
Finnish	0.000416	0.000416
European (Non-Finnish)	0.000707	0.000659
Middle Eastern	0.000436	0.000435
South Asian	0.000294	0.000294
Other	0.000659	0.000652

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Dioxygenase that catalyzes the conversion of the modified genomic base 5-methylcytosine (5mC) into 5- hydroxymethylcytosine (5hmC) and plays a key role in active DNA demethylation. Has a preference for 5-hydroxymethylcytosine in CpG motifs. Also mediates subsequent conversion of 5hmC into 5- formylcytosine (5fC), and conversion of 5fC to 5-carboxylcytosine (5caC). Conversion of 5mC into 5hmC, 5fC and 5caC probably constitutes the first step in cytosine demethylation. Methylation at the C5 position of cytosine bases is an epigenetic modification of the mammalian genome which plays an important role in transcriptional regulation. In addition to its role in DNA demethylation, also involved in the recruitment of the O-GlcNAc transferase OGT to CpG-rich transcription start sites of active genes, thereby promoting histone H2B GlcNAcylation by OGT. {ECO:0000269|PubMed:19483684, ECO:0000269|PubMed:21057493, ECO:0000269|PubMed:21817016, ECO:0000269|PubMed:23222540, ECO:0000269|PubMed:23353889, ECO:0000269|PubMed:24315485}.
• Disease: DISEASE: Note=TET2 is frequently mutated in myeloproliferative disorders (MPD). These constitute a heterogeneous group of disorders, also known as myeloproliferative diseases or myeloproliferative neoplasms (MPN), characterized by cellular proliferation of one or more hematologic cell lines in the peripheral blood, distinct from acute leukemia. Included diseases are: essential thrombocythemia, polycythemia vera, primary myelofibrosis (chronic idiopathic myelofibrosis). Bone marrow samples from patients display uniformly low levels of hmC in genomic DNA compared to bone marrow samples from healthy controls as well as hypomethylation relative to controls at the majority of differentially methylated CpG sites.; 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. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Note=TET2 is frequently mutated in systemic mastocytosis; also known as systemic mast cell disease. A condition with features in common with myeloproliferative diseases. It is a clonal disorder of the mast cell and its precursor cells. The clinical symptoms and signs of systemic mastocytosis are due to accumulation of clonally derived mast cells in different tissues, including bone marrow, skin, the gastrointestinal tract, the liver, and the spleen.; DISEASE: Myelodysplastic syndrome (MDS) [MIM:614286]: A heterogeneous group of closely related clonal hematopoietic disorders. All are characterized by a hypercellular or hypocellular bone marrow with impaired morphology and maturation, dysplasia of the myeloid, megakaryocytic and/or erythroid lineages, and peripheral blood cytopenias resulting from ineffective blood cell production. Included diseases are: refractory anemia (RA), refractory anemia with ringed sideroblasts (RARS), refractory anemia with excess blasts (RAEB), refractory cytopenia with multilineage dysplasia and ringed sideroblasts (RCMD-RS); chronic myelomonocytic leukemia (CMML) is a myelodysplastic/myeloproliferative disease. MDS is considered a premalignant condition in a subgroup of patients that often progresses to acute myeloid leukemia (AML). {ECO:0000269|PubMed:19372255, ECO:0000269|PubMed:19483684, ECO:0000269|PubMed:21057493}. Note=The disease is caused by mutations affecting the gene represented in this entry. Bone marrow samples from patients display uniformly low levels of hmC in genomic DNA compared to bone marrow samples from healthy controls as well as hypomethylation relative to controls at the majority of differentially methylated CpG sites.
• Pathway: MECP2 and Associated Rett Syndrome;TET1,2,3 and TDG demethylate DNA;Epigenetic regulation of gene expression;Gene expression (Transcription) (Consensus)

Recessive Scores

• pRec: 0.0630

Intolerance Scores

• loftool: 0.998
• rvis_EVS: 1.97
• rvis_percentile_EVS: 97.56

Haploinsufficiency Scores

• pHI: 0.0619
• hipred: N
• hipred_score: 0.123
• ghis: 0.426

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: N
• gene_indispensability_score: 0.0000286

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Tet2
• Phenotype: renal/urinary system phenotype; immune system phenotype; liver/biliary system phenotype; neoplasm; 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); normal phenotype; growth/size/body region phenotype; hematopoietic system phenotype; cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); cellular phenotype; endocrine/exocrine gland phenotype

Zebrafish Information Network

• Gene name: tet2
• Affected structure: nucleate erythrocyte
• Phenotype tag: abnormal
• Phenotype quality: increased amount

Gene ontology

• Biological process: 5-methylcytosine catabolic process;protein O-linked glycosylation;cell cycle;response to organic cyclic compound;myeloid cell differentiation;positive regulation of transcription by RNA polymerase II;oxidation-reduction process;oxidative demethylation;DNA demethylation;histone H3-K4 trimethylation
• Cellular component: nucleus
• Molecular function: DNA binding;iron ion binding;protein binding;ferrous iron binding;zinc ion binding;methylcytosine dioxygenase activity