Human Gene Module / Chromosome 4 / TET2

TET2Tet methylcytosine dioxygenase 2

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
6 / 7
Rare Variants / Common Variants
9 / 0
Aliases
TET2, KIAA1546,  MDS
Associated Syndromes
-
Chromosome Band
4q24
Associated Disorders
-
Relevance to Autism

Two de novo missense variants in the TET2 gene have been identified in ASD probands from the Simons Simplex Collection, with no de novo events in this gene observed in 1,786 unaffected siblings (P=0.02) (Iossifov et al., 2014; Krumm et al., 2015).

Molecular Function

The protein encoded by this gene is a methylcytosine 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. In addition to its role in DNA demethylation, TET2 isalso 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.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
Mouse
Entrez GeneAllen Brain Atlas
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to TET2 (7 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
2 Support Excess of rare, inherited truncating mutations in autism Krumm N , et al. (2015) Yes -
3 Support Genome-wide characteristics of de novo mutations in autism Yuen RK et al. (2016) Yes -
4 Support Exonic Mosaic Mutations Contribute Risk for Autism Spectrum Disorder Krupp DR , et al. (2017) Yes -
5 Support - N.Y.) (07/2) No -
6 Support - Zhou X et al. (2022) Yes -
7 Support - Xu X et al. (2023) Yes -
Rare Variants   (9)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.1648C>T p.Arg550Ter stop_gained De novo - - 35901164 N.Y.) (07/2)
c.5725G>T p.Glu1909Ter stop_gained De novo - - 35901164 N.Y.) (07/2)
c.2861G>A p.Trp954Ter stop_gained De novo - - 35982159 Zhou X et al. (2022)
c.3785G>C p.Arg1262Pro missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.2392G>A p.Glu798Lys missense_variant De novo - Simplex 27525107 Yuen RK et al. (2016)
c.789G>T p.Glu263Asp missense_variant De novo - Simplex 25961944 Krumm N , et al. (2015)
c.1422G>A p.Pro474%3D synonymous_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.3847G>T p.Ala1283Ser missense_variant Familial - Simplex 28867142 Krupp DR , et al. (2017)
c.5008C>T p.Leu1670Phe missense_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
Common Variants  

No common variants reported.

SFARI Gene score
2

Strong Candidate

Two de novo missense variants in the TET2 gene have been identified in ASD probands from the Simons Simplex Collection, with no de novo events in this gene observed in 1,786 unaffected siblings (P-value 0.02) (Iossifov et al., 2014; Krumm et al., 2015). A third de novo missense variant in TET2 was observed in an ASD proband from a cohort of 200 Canadian ASD trio families (Yuen et al., 2016).

Score Delta: Score remained at 2

criteria met
See SFARI Gene'scoring criteria
2

Strong Candidate

See all Category 2 Genes

We considered a rigorous statistical comparison between cases and controls, yielding genome-wide statistical significance, with independent replication, to be the strongest possible evidence for a gene. These criteria were relaxed slightly for category 2.

10/1/2019
3
icon
2

Decreased from 3 to 2

New Scoring Scheme
Description

Two de novo missense variants in the TET2 gene have been identified in ASD probands from the Simons Simplex Collection, with no de novo events in this gene observed in 1,786 unaffected siblings (P-value 0.02) (Iossifov et al., 2014; Krumm et al., 2015). A third de novo missense variant in TET2 was observed in an ASD proband from a cohort of 200 Canadian ASD trio families (Yuen et al., 2016).

Reports Added
[New Scoring Scheme]
10/1/2017
icon
3

Increased from to 3

Description

Two de novo missense variants in the TET2 gene have been identified in ASD probands from the Simons Simplex Collection, with no de novo events in this gene observed in 1,786 unaffected siblings (P-value 0.02) (Iossifov et al., 2014; Krumm et al., 2015). A third de novo missense variant in TET2 was observed in an ASD proband from a cohort of 200 Canadian ASD trio families (Yuen et al., 2016).

Reports Added
[Exonic Mosaic Mutations Contribute Risk for Autism Spectrum Disorder.2017]
Krishnan Probability Score

Score 0.49454799998635

Ranking 3597/25841 scored genes


[Show Scoring Methodology]
Krishnan and colleagues generated probability scores genome-wide by using a machine learning approach on a human brain-specific gene network. The method was first presented in Nat Neurosci 19, 1454-1462 (2016), and scores for more than 25,000 RefSeq genes can be accessed in column G of supplementary table 3 (see: http://www.nature.com/neuro/journal/v19/n11/extref/nn.4353-S5.xlsx). A searchable browser, with the ability to view networks of associated ASD risk genes, can be found at asd.princeton.edu.
Original Source
ExAC Score

Score 7.0536825129139E-26

Ranking 18108/18225 scored genes


[Show Scoring Methodology]
The Exome Aggregation Consortium (ExAC) is a summary database of 60,706 exomes that has been widely used to estimate 'constraint' on mutation for individual genes. It was introduced by Lek et al. Nature 536, 285-291 (2016), and the ExAC browser can be found at exac.broadinstitute.org. The pLI score was developed as measure of intolerance to loss-of- function mutation. A pLI > 0.9 is generally viewed as highly constrained, and thus any loss-of- function mutations in autism in such a gene would be more likely to confer risk. For a full list of pLI scores see: ftp://ftp.broadinstitute.org/pub/ExAC_release/release0.3.1/functional_gene_constraint/fordist_cle aned_exac_nonTCGA_z_pli_rec_null_data.txt
Original Source
Sanders TADA Score

Score 0.86826274128752

Ranking 4218/18665 scored genes


[Show Scoring Methodology]
The TADA score ('Transmission and De novo Association') was introduced by He et al. PLoS Genet 9(8):e1003671 (2013), and is a statistic that integrates evidence from both de novo and transmitted mutations. It forms the basis for the claim of 65 individual genes being strongly associated with autism risk at a false discovery rate of 0.1 (Sanders et al. Neuron 87, 1215-1233 (2015)). The calculated TADA score for 18,665 RefSeq genes can be found in column P of Supplementary Table 6 in the Sanders et al. paper (the column headed 'tadaFdrAscSscExomeSscAgpSmallDel'), which represents a combined analysis of exome data and small de novo deletions (see www.cell.com/cms/attachment/2038545319/2052606711/mmc7.xlsx).
Original Source
Zhang D Score

Score 0.17045906638146

Ranking 4790/20870 scored genes


[Show Scoring Methodology]
The DAMAGES score (disease-associated mutation analysis using gene expression signatures), or D score, was developed to combine evidence from de novo loss-of- function mutation with evidence from cell-type- specific gene expression in the mouse brain (specifically translational profiles of 24 specific mouse CNS cell types isolated from 6 different brain regions). Genes with positive D scores are more likely to be associated with autism risk, with higher-confidence genes having higher D scores. This statistic was first presented by Zhang & Shen (Hum Mutat 38, 204- 215 (2017), and D scores for more than 20,000 RefSeq genes can be found in column M in supplementary table 2 from that paper.
Original Source
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