Human Gene Module / Chromosome 17 / TANC2

TANC2etratricopeptide repeat, ankyrin repeat and coiled-coil containing 2

SFARI Gene Score
1S
High Confidence, Syndromic Criteria 1.1, Syndromic
Autism Reports / Total Reports
12 / 16
Rare Variants / Common Variants
40 / 0
EAGLE Score
24.95
Strong Learn More
Aliases
TANC2, ROLSA,  rols
Associated Syndromes
-
Chromosome Band
17q23.2-q23.3
Associated Disorders
DD/NDD, EP, EPS
Genetic Category
Rare Single Gene Mutation, Syndromic, Functional
Relevance to Autism

A de novo loss-of-function variant in this gene was identified in an ASD proband from the Simons Simplex Collection in Iossifov et al., 2014. A likely damaging missense variant in this gene was subsequently identified in an ASD proband from the Autism Genetic Resource Exchange (AGRE) in Stessman et al., 2017.

Molecular Function

This gene encodes a protien of unknown function.

External Links
Gene CardOpen Targets PlatformgnomAD browserSynGO portalPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to TANC2 (16 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support Diagnostic exome sequencing in persons with severe intellectual disability de Ligt J , et al. (2012) No -
2 Support De novo mutations in schizophrenia implicate synaptic networks Fromer M , et al. (2014) No -
3 Primary The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
4 Support Excess of rare, inherited truncating mutations in autism Krumm N , et al. (2015) Yes -
5 Recent Recommendation Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases Stessman HA , et al. (2017) Yes -
6 Support Rates, distribution and implications of postzygotic mosaic mutations in autism spectrum disorder Lim ET , et al. (2017) Yes -
7 Support Contribution of rare inherited and de novo variants in 2,871 congenital heart disease probands Jin SC , et al. (2017) No Neurodevelopmental disorders (NDD)
8 Recent Recommendation A Statistical Framework for Mapping Risk Genes from De Novo Mutations in Whole-Genome-Sequencing Studies Liu Y , et al. (2018) Yes -
9 Support Regulation of KIF1A-Driven Dense Core Vesicle Transport: Ca 2+/CaM Controls DCV Binding and Liprin-?/TANC2 Recruits DCVs to Postsynaptic Sites Stucchi R , et al. (2018) Yes -
10 Recent Recommendation Disruptive mutations in TANC2 define a neurodevelopmental syndrome associated with psychiatric disorders Guo H , et al. (2019) Yes Epilepsy/seizures
11 Support - Bertoli-Avella AM et al. (2021) Yes -
12 Support - Mahjani B et al. (2021) Yes -
13 Support - Garrett L et al. (2022) No -
14 Support - Zhou X et al. (2022) Yes -
15 Support - Long F et al. (2023) Yes -
16 Support - Wang J et al. (2023) Yes -
Rare Variants   (40)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - missense_variant De novo - - 29754769 Liu Y , et al. (2018)
- - splicing_variant De novo - - 29754769 Liu Y , et al. (2018)
- - copy_number_loss De novo - Simplex 31616000 Guo H , et al. (2019)
- - copy_number_loss Unknown - Unknown 31616000 Guo H , et al. (2019)
- - loss_of_function_variant De novo - - 29754769 Liu Y , et al. (2018)
c.1219+1G>A - splice_site_variant De novo - - 31616000 Guo H , et al. (2019)
c.4016+2T>G - splice_site_variant De novo - - 31616000 Guo H , et al. (2019)
c.333C>A p.Tyr111Ter stop_gained De novo - - 28991257 Jin SC , et al. (2017)
c.3067C>T p.Arg1023Ter stop_gained Unknown - - 31616000 Guo H , et al. (2019)
c.4198C>T p.Gln1400Ter stop_gained De novo - - 31616000 Guo H , et al. (2019)
c.4447C>T p.Gln1483Ter stop_gained De novo - - 31616000 Guo H , et al. (2019)
- - copy_number_loss Familial Paternal Multiplex 31616000 Guo H , et al. (2019)
c.916C>T p.Arg306Cys missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.5515C>T p.Arg1839Ter stop_gained Unknown - - 34615535 Mahjani B et al. (2021)
c.2264G>A p.Arg755His missense_variant De novo - - 31616000 Guo H , et al. (2019)
c.1219+1G>A - splice_site_variant De novo - Simplex 31616000 Guo H , et al. (2019)
c.2566C>T p.Arg856Ter stop_gained De novo - Simplex 37393044 Wang J et al. (2023)
c.2882G>A p.Arg961Gln missense_variant De novo - - 28191889 Stessman HA , et al. (2017)
c.3196C>T p.Arg1066Ter stop_gained De novo - Simplex 25363768 Iossifov I et al. (2014)
c.946del p.Ala316HisfsTer10 frameshift_variant De novo - - 35982159 Zhou X et al. (2022)
c.3828del p.Glu1277LysfsTer7 frameshift_variant De novo - - 31616000 Guo H , et al. (2019)
c.4405del p.Arg1469GlyfsTer6 frameshift_variant De novo - - 31616000 Guo H , et al. (2019)
c.1544dup p.Arg516ProfsTer13 frameshift_variant De novo - - 35982159 Zhou X et al. (2022)
c.4556C>T p.Pro1519Leu missense_variant De novo - Simplex 28714951 Lim ET , et al. (2017)
c.4449del p.Gln1483HisfsTer69 frameshift_variant De novo - - 31616000 Guo H , et al. (2019)
c.3543+1G>T - splice_site_variant Familial Maternal Simplex 31616000 Guo H , et al. (2019)
c.2381C>T p.Ala794Val missense_variant De novo - Simplex 24463507 Fromer M , et al. (2014)
c.547+1G>A - splice_site_variant Familial Paternal Simplex 25961944 Krumm N , et al. (2015)
c.2278C>T p.Arg760Cys missense_variant De novo - Simplex 23033978 de Ligt J , et al. (2012)
c.5066A>G p.His1689Arg missense_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.3769-1G>C - splice_site_variant Unknown - Simplex 33875846 Bertoli-Avella AM et al. (2021)
c.2470-1G>A - splice_site_variant De novo - Unknown 33875846 Bertoli-Avella AM et al. (2021)
c.3016-1G>A - splice_site_variant Unknown - Unknown 33875846 Bertoli-Avella AM et al. (2021)
c.1589_1590del p.Arg530LysfsTer5 frameshift_variant De novo - - 31616000 Guo H , et al. (2019)
c.5319_5344dup p.Phe1782CysfsTer6 frameshift_variant De novo - - 31616000 Guo H , et al. (2019)
c.4713_4716del p.Gln1572PhefsTer41 frameshift_variant Unknown - Unknown 31616000 Guo H , et al. (2019)
c.2781del p.Ala928GlnfsTer4 frameshift_variant Familial Maternal Multiplex 31616000 Guo H , et al. (2019)
c.2349_2350dup p.Cys784SerfsTer22 frameshift_variant Familial Paternal Simplex 31616000 Guo H , et al. (2019)
c.747_748del p.Leu251IlefsTer34 frameshift_variant De novo - Simplex 33875846 Bertoli-Avella AM et al. (2021)
c.4586del p.Pro1529GlnfsTer23 frameshift_variant Familial Maternal Multiplex 33875846 Bertoli-Avella AM et al. (2021)
Common Variants  

No common variants reported.

SFARI Gene score
1S

High Confidence, Syndromic

Score Delta: Score remained at 1S

criteria met
See SFARI Gene'scoring criteria
1

High Confidence

See all Category 1 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.

S

Syndromic

See all Category S Genes

The syndromic category includes mutations that are associated with a substantial degree of increased risk and consistently linked to additional characteristics not required for an ASD diagnosis. If there is independent evidence implicating a gene in idiopathic ASD, it will be listed as "#S" (e.g., 2S, 3S, etc.). If there is no such independent evidence, the gene will be listed simply as "S."

4/1/2021
1
icon
1

Score remained at 1

Description

A de novo loss-of-function variant in this gene was identified in an ASD proband from the Simons Simplex Collection in Iossifov et al., 2014. A likely damaging missense variant in this gene was subsequently identified in an ASD proband from the Autism Genetic Resource Exchange (AGRE) in Stessman et al., 2017. TADA-Annotations (TADA-A) analysis of whole-genome sequencing data from five studies with a total of 314 ASD-affected subjects in Liu et al., 2018 identified TANC2 as an ASD risk gene with a false discovery rate (FDR) < 0.1; among the de novo variants associated with this gene in ASD subjects was a loss-of-function variant, a predicted damaging (Mis3) missense variant, and a splicing SNV. Guo et al., 2019 presented detailed clinical and genetic data for 20 patients with likely gene-disruptive variants in the TANC2 gene and found that while pediatric patients presented with a neurodevelopmental syndrome characterized by autism or autistic features, intellectual disability, language and motor delay, and a variable degree of epilepsy, a pattern of more complex psychiatric dysfunction or behavioral problems was frequently observed in adult probands or carrier parents.

Reports Added
[Combining exome/genome sequencing with data repository analysis reveals novel gene-disease associations for a wide range of genetic disorders2021]
10/1/2019
3
icon
1

Decreased from 3 to 1

New Scoring Scheme
Description

A de novo loss-of-function variant in this gene was identified in an ASD proband from the Simons Simplex Collection in Iossifov et al., 2014. A likely damaging missense variant in this gene was subsequently identified in an ASD proband from the Autism Genetic Resource Exchange (AGRE) in Stessman et al., 2017. TADA-Annotations (TADA-A) analysis of whole-genome sequencing data from five studies with a total of 314 ASD-affected subjects in Liu et al., 2018 identified TANC2 as an ASD risk gene with a false discovery rate (FDR) < 0.1; among the de novo variants associated with this gene in ASD subjects was a loss-of-function variant, a predicted damaging (Mis3) missense variant, and a splicing SNV. Guo et al., 2019 presented detailed clinical and genetic data for 20 patients with likely gene-disruptive variants in the TANC2 gene and found that while pediatric patients presented with a neurodevelopmental syndrome characterized by autism or autistic features, intellectual disability, language and motor delay, and a variable degree of epilepsy, a pattern of more complex psychiatric dysfunction or behavioral problems was frequently observed in adult probands or carrier parents.

Reports Added
[De novo mutations in schizophrenia implicate synaptic networks.2014] [Excess of rare, inherited truncating mutations in autism.2015] [Regulation of KIF1A-Driven Dense Core Vesicle Transport: Ca2+/CaM Controls DCV Binding and Liprin-/TANC2 Recruits DCVs to Postsynaptic Sites.2018] [Disruptive mutations in TANC2 define a neurodevelopmental syndrome associated with psychiatric disorders.2019] [New Scoring Scheme]
7/1/2018
4
icon
3

Decreased from 4 to 3

Description

A de novo loss-of-function variant in this gene was identified in an ASD proband from the Simons Simplex Collection in Iossifov et al., 2014. A likely damaging missense variant in this gene was subsequently identified in an ASD proband from the Autism Genetic Resource Exchange (AGRE) in Stessman et al., 2017. TADA-Annotations (TADA-A) analysis of whole-genome sequencing data from five studies with a total of 314 ASD-affected subjects in Liu et al., 2018 identified TANC2 as an ASD risk gene with a false discovery rate (FDR) < 0.1; among the de novo variants associated with this gene in ASD subjects was a loss-of-function variant, a predicted damaging (Mis3) missense variant, and a splicing SNV.

10/1/2017
4
icon
4

Decreased from 4 to 4

Description

A de novo loss-of-function variant in this gene was identified in an ASD proband from the Simons Simplex Collection in Iossifov et al., 2014. A likely damaging missense variant in this gene was subsequently identified in an ASD proband from the Autism Genetic Resource Exchange (AGRE) in Stessman et al., 2017.

Reports Added
[Contribution of rare inherited and de novo variants in 2,871 congenital heart disease probands.2017]
7/1/2017
4
icon
4

Decreased from 4 to 4

Description

A de novo loss-of-function variant in this gene was identified in an ASD proband from the Simons Simplex Collection in Iossifov et al., 2014. A likely damaging missense variant in this gene was subsequently identified in an ASD proband from the Autism Genetic Resource Exchange (AGRE) in Stessman et al., 2017.

Reports Added
[Rates, distribution and implications of postzygotic mosaic mutations in autism spectrum disorder.2017]
1/1/2017
icon
4

Increased from to 4

Description

A de novo loss-of-function variant in this gene was identified in an ASD proband from the Simons Simplex Collection in Iossifov et al., 2014. A likely damaging missense variant in this gene was subsequently identified in an ASD proband from the Autism Genetic Resource Exchange (AGRE) in Stessman et al., 2017.

Krishnan Probability Score

Score 0.49210163259974

Ranking 4740/25841 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 0.99999996584406

Ranking 164/18225 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
Iossifov Probability Score

Score 0.827

Ranking 214/239 scored genes


[Show Scoring Methodology]
Supplementary dataset S2 in the paper by Iossifov et al. (PNAS 112, E5600-E5607 (2015)) lists 239 genes with a probability of at least 0.8 of being associated with autism risk (column I). This probability metric combines the evidence from de novo likely-gene- disrupting and missense mutations and assesses it against the background mutation rate in unaffected individuals from the University of Washington’s Exome Variant Sequence database (evs.gs.washington.edu/EVS/). The list of probability scores can be found here: www.pnas.org/lookup/suppl/doi:10.1073/pnas.1516376112/- /DCSupplemental/pnas.1516376112.sd02.xlsx
Original Source
Sanders TADA Score

Score 0.32151395652325

Ranking 197/18665 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 0.36416823654834

Ranking 1857/20870 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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