TET2

protein-coding

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

Gene summary

The protein encoded by this gene is a methylcytosine dioxygenase that catalyzes the conversion of methylcytosine to 5-hydroxymethylcytosine. The encoded protein is involved in myelopoiesis, and defects in this gene have been associated with several myeloproliferative disorders. Two variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2011]

Previous symbols:

KIAA1546

MANE transcript

NM_001127208.3

Inheritance

AR, AD

ClinVar variants

P:183U:1276B:664

Top phenotype

Immunodeficiency 75 with lymphoproliferation

gnomAD constraint

pLI —, LoF o/e 1.14

Max pathogenic AF

—

Genomic locus

chr4:105,145,875-105,279,816

External References & Databases

Ensembl (ENSG00000168769)

Transcript & Mutation Effects

hg38 • Region Span ~133.9 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

immunodeficiency 75STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0030858

Submitter: Labcorp Genetics (formerly Invitae)

pulmonary arterial hypertensionMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0015924

Submitter: ClinGen

TET2 is involved in clonal hematopoiesis of indeterminate potential and has been curated independently for a role of somatic variants in cancer. Since the mechanism in pulmonary arterial hypertension (PAH) is through autosomal dominantly acting germline variants, the curations were split instead of lumped. TET2 was first reported in relation to autosomal dominant pulmonary arterial hypertension (PAH) in 2020 (Potus et al., PMID: 32192357). Out of a cohort of 2572 cases from the PAH biobank, 6 rare predicted deleterious likely germline variants including missense, nonsense, and frameshift variants were identified in 6 unrelated individuals. The relationship between TET2 and PAH is also supported by experimental evidence including tissue expression in controls and patients, biochemical function as a negative regulator of a proinflammatory response, and Tet2 knockout mice exhibiting a PH phenotype. In summary, there is moderate evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the ClinGen PH Gene Curation Expert Panel on 4/6/2022. The gene-disease relationship was re-evaluated on 12 February 2025 by the ClinGen PH Gene Curation Expert Panel (SOP v10). This record underwent administrative updates to correct typographical errors. New genetic data (PMIDs: 38116660, 39849426) and expression data (PMIDs: 35581740, 37146099) were reviewed but did not add any new evidence for a gene-disease relationship with H/IPAH. As a result of this re-evaluation, the classification did not change.

immunodeficiency 75STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0030858

Submitter: PanelApp Australia

pulmonary arterial hypertensionMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0015924

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Immunodeficiency 75 with lymphoproliferationAR

Manifestation: Allergy/Immunology/Infectious; Neurologic; Oncologic

Intervention: Allergy/Immunology/Infectious; Oncologic

Rationale: 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

Refs: 32518946

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TET2 variants in ClinVar

14 Conditions Cataloged

not specifiedTotal: 1437

not providedTotal: 876

TET2-related disorderTotal: 57

Immunodeficiency 75Total: 22

EBV-positive nodal T- and NK-cell lymphomaTotal: 19

Myelodysplastic syndromeTotal: 9

Angioimmunoblastic T-cell lymphomaTotal: 3

Atypical chronic myeloid leukemia, BCR-ABL1 negativeTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001127208.3. 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			1 clinvar	607 clinvar	4 clinvar	612
missense	1 clinvar		1200 clinvar	48 clinvar	5 clinvar	1254
nonsense	49 clinvar	9 clinvar	39 clinvar			97
start loss						0
frameshift	104 clinvar	10 clinvar	35 clinvar			149
splice donor/acceptor (+/-2bp)		10 clinvar	1 clinvar			11
Total	154	29	1276	655	9	2123

Highest pathogenic variant AF is 0.000017347278

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 23 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001127208.3	RefSeq	NP_001120680.1	9	MANE Select
ENST00000380013.9	Ensembl	ENSP00000369351.4	9	MANE Select
NM_017628.4	RefSeq	NP_060098.3	1	Standard
ENST00000265149.9	Ensembl	ENSP00000265149.5	3	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
tet2	Danio rerio	Structure: nucleate erythrocyte Quality: increased amount abnormal

Gene / Model

Organism

Observed Phenotype

tet2

Danio rerio

Structure: nucleate erythrocyte

Quality: increased amount

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

MECP2 and Associated Rett Syndrome
TET1,2,3 and TDG demethylate DNA
Epigenetic regulation of gene expression
Gene expression (Transcription)

Biological Process

5-methylcytosine catabolic process
protein O-linked glycosylation
cell cycle
response to organic cyclic compound
myeloid cell differentiation

Molecular Function

DNA binding
iron ion binding
protein binding
ferrous iron binding
zinc ion binding

Cellular Component

nucleus

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000540549
Coding exons: 9
Length: 133942
Individuals with no LoFs: 125608
Homozygous LoFs: 0
Heterozygous LoFs: 139
Defined: 125747
p: 0.000553

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.62	872	1.02e+3	0.857	0.0000506	13154
Missense (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

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00037	0.00037	rare
Latino/Admixed American	0.00049	0.00049	rare
Ashkenazi Jewish	0.0011	0.0011	notable
East Asian	0.00044	0.00044	rare
Finnish	0.00042	0.00042	rare
European (Non-Finnish)	0.00071	0.00066	rare
South Asian	0.00029	0.00029	rare
Other	0.00066	0.00065	rare

dbNSFP Gene Annotations

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.;

Recessive Scores

pRec: 0.0630

Intolerance Scores

LoFtool: 0.998
RVIS EVS: 1.97
RVIS percentile EVS: 97.56

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.0000286

Gene Damage Prediction

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