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Intellectual disability

Gene: TANC2

Amber List (moderate evidence)

TANC2 (tetratricopeptide repeat, ankyrin repeat and coiled-coil containing 2)
EnsemblGeneIds (GRCh38): ENSG00000170921
EnsemblGeneIds (GRCh37): ENSG00000170921
OMIM: 615047, Gene2Phenotype
TANC2 is in 3 panels

6 reviews

Arina Puzriakova (Genomics England Curator)

Green List (high evidence)

Comment on list classification: This gene should be promoted to Green at the next GMS panel update - multiple unrelated families with a comparable neurodevelopmental disorder (including ID). As highlighted in review by Zornitza Stark, most reported SNVs are de novo putative disruptive variants, or missense variants that are predicted in silico to have a damaging or possibly damaging effect. Gene expression and function are neurodevelopmentally-relevant, and there is some limited functional data.

Gene-disease association is also now listed in both OMIM and Gene2Phenotype.
Created: 25 Jan 2021, 12:09 p.m. | Last Modified: 25 Jan 2021, 12:09 p.m.
Panel Version: 3.731
Removed 'watchlist' tag and added 'for-review' tag as there is now sufficient evidence to promote this gene to Green
Created: 25 Jan 2021, 11:43 a.m. | Last Modified: 25 Jan 2021, 11:43 a.m.
Panel Version: 3.729
TANC2 is now associated with a relevant phenotype in OMIM and has a 'possible' disease confidence rating for 'TANC2-related neurodevelopmental and psychiatric disorder' in Gene2Phenotype.

20 individuals described in PMID: 31616000 (2019) with a neurodevelopmental disorder (including ID/GDD) and various 'likely gene-disruptive' variants in this gene (previously reviewed below)

PMID: 33160097 (2020) reports a further individual with a 17q23.3 de novo microdeletion disrupting exons 3–7 of the TANC2 gene. The patient presented craniofacial dysmorphic features, hypotonia, absent speech and gait, and profound ID - supporting the role of TANC2 in neurodevelopmental phenotypes.

TANC2 encodes a synaptic scaffold protein that interacts and co-localises with multiple postsynaptic-density proteins in dendrites to regulate dendritic spines and excitatory synapse formation. Stucchi et al. (2018) (PMID:30021165) showed that proteins with disruptive variants (including p.R1066* reported in patient from PMID:31616000) failed to accumulate at the dendritic spines
Created: 25 Jan 2021, 11:36 a.m. | Last Modified: 25 Jan 2021, 11:36 a.m.
Panel Version: 3.729

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Intellectual developmental disorder with autistic features and language delay, with or without seizures, OMIM:618906

Publications

Zornitza Stark (Australian Genomics)

Green List (high evidence)

19 families with neurodevelopmental phenotypes and variants in this gene. The majority of variants are de novo, highly damaging (truncating/splice site) variants, which would easily meet ACMG criteria for pathogenicity. Gene is highly conserved and intolerant to truncating mutations (pLI score = 1, RVIS% = 0.4). Overall, the evidence for gene-disease association is very strong, despite OMIM/G2P lagging behind.
Created: 29 Feb 2020, 9:28 a.m. | Last Modified: 29 Feb 2020, 9:28 a.m.
Panel Version: 3.3

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Intellectual disability; autism; epilepsy

Publications

Variants in this GENE are reported as part of current diagnostic practice

Andrea Haworth (ACGS, Congenica)

Recent publication PMC6794285 https://www.nature.com/articles/s41467-019-12435-8
Describes loss of function variants in TANC2 in 20 pediatric patients presenting with autism, intellectual disability, and delayed language and motor development. Variants observed included missense, nonsense, splice, frameshift and structural variation. variants were de novo or inherited from an affected parent.

Paper describes genetic and clinical features of cases. Suggest that this gene should be elevated to amber or red after review.
Created: 23 Oct 2019, 5:53 p.m. | Last Modified: 23 Oct 2019, 5:53 p.m.
Panel Version: 2.1066

Caroline Wright (Sanger)

Red List (low evidence)

Rebecca Foulger (Genomics England curator)

I don't know

Comment on list classification: Updated rating from Red to Amber based on PMID:31616000 2019 article suggested by Andrea Haworth. Sufficient unrelated cases (19/20) with an ID/DD phenotype but the pathogenicity of the variants has not yet been verified. Not yet associated with a disorder in Gene2Phenotype or OMIM. Currently only 1 paper, therefore Amber with 'watchlist' tag is appropriate pending functional studies.
Created: 24 Oct 2019, 11:10 a.m. | Last Modified: 24 Oct 2019, 11:10 a.m.
Panel Version: 2.1076
Summary of PMID:31616000 (PMC:6794285) suggested by Andrea Haworth reviewer: Guo et al assembled phenotypic data for 19 probands and 1 affected sibling with TANC2 variants. Variants include 16 LGD (likely gene-disruptive) variants and three intragenic microdeletions. Phenotypes included ASD, ID, speech-language delay and childhood motor delay:
- 15/20 individuals had ASD/autism features (7 with a formal diagnosis).
- 19/20 individuals had some form of ID (17 with a formal diagnosis of borderline to severe ID, and 2 with learning difficulties without a formal diagnosis).
- 18/20 showed speech-language delay.
- 13/19 individuals had childhood motor delay.
- 11/20 individuals had a formal diagnosis of epilepsy (9) or suffered recurrent seizures (2).
Created: 24 Oct 2019, 11:07 a.m. | Last Modified: 24 Oct 2019, 11:07 a.m.
Panel Version: 2.1075
Comment on mode of inheritance: Set MOI as MONOALLELIC based on PMID:31616000 (Figure 2).
Created: 24 Oct 2019, 11:04 a.m. | Last Modified: 24 Oct 2019, 11:04 a.m.
Panel Version: 2.1074
Listed as a candidate ID gene in PMID:26350204 but insufficient ID evidence for inclusion on diagnostic panel.
Created: 31 Oct 2017, 9:24 a.m.

Publications

Lu Raymond (university of cambridge )

Red List (low evidence)

Details

Mode of Inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Sources
  • Expert Review Amber
Phenotypes
  • Intellectual developmental disorder with autistic features and language delay, with or without seizures, 618906
Tags
for-review
OMIM
615047
Clinvar variants
Variants in TANC2
Penetrance
Complete
Publications
Panels with this gene

History Filter Activity

25 Jan 2021, Gel status: 2

Entity classified by Genomics England curator

Arina Puzriakova (Genomics England Curator)

Gene: tanc2 has been classified as Amber List (Moderate Evidence).

25 Jan 2021, Gel status: 2

Set publications

Arina Puzriakova (Genomics England Curator)

Publications for gene: TANC2 were set to 26350204; 31616000

25 Jan 2021, Gel status: 2

Removed Tag, Added Tag

Arina Puzriakova (Genomics England Curator)

Tag watchlist was removed from gene: TANC2. Tag for-review tag was added to gene: TANC2.

16 Sep 2020, Gel status: 2

Added Tag

Arina Puzriakova (Genomics England Curator)

Tag watchlist tag was added to gene: TANC2.

16 Sep 2020, Gel status: 2

Set Phenotypes

Arina Puzriakova (Genomics England Curator)

Phenotypes for gene: TANC2 were changed from NDD syndrome; Neurodevelopmental Disorder; Intellectual disability; Childhood speech delay; Childhood motor delay to Intellectual developmental disorder with autistic features and language delay, with or without seizures, 618906

24 Oct 2019, Gel status: 2

Entity classified by Genomics England curator

Rebecca Foulger (Genomics England curator)

Gene: tanc2 has been classified as Amber List (Moderate Evidence).

24 Oct 2019, Gel status: 1

Set Phenotypes

Rebecca Foulger (Genomics England curator)

Phenotypes for gene: TANC2 were changed from to NDD syndrome; Neurodevelopmental Disorder; Intellectual disability; Childhood speech delay; Childhood motor delay

24 Oct 2019, Gel status: 1

Set mode of inheritance

Rebecca Foulger (Genomics England curator)

Mode of inheritance for gene: TANC2 was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

24 Oct 2019, Gel status: 1

Set publications

Rebecca Foulger (Genomics England curator)

Publications for gene: TANC2 were set to 26350204

12 Mar 2018, Gel status: 1

Panel promoted to version 2.0

Ellen McDonagh (Genomics England Curator)

12.03.2018: Due to major updates completed (Phase 1, 2 and 3), this panel was promoted to Version 2 in order to reflect the major updates since November 2017 which have resulted in reviews for 836 genes added by Genomics England Curators and the Clinical Team, 130 new Green genes added to the interpretation pipeline (from 751 to 881 Green genes), and the gene total has increased from 1879 to 1927.

29 Nov 2017, Gel status: 1

Set publications

Ellen McDonagh (Genomics England Curator)

Publications for gene TANC2 was set to ['26350204']

13 Nov 2015, Gel status: 1

gel status update

GEL ()

The Gel status was updated for this whole panel

13 Nov 2015, Gel status: 2

gel status update

GEL ()

The Gel status was updated for this whole panel

13 Nov 2015, Gel status: 0

Created

Ellen McDonagh (Genomics England Curator)

TANC2 was created by ellenmcdonagh

13 Nov 2015, Gel status: 0

Added New Source

Ellen McDonagh (Genomics England Curator)

TANC2 was added to Intellectual disabilitypanel. Sources: Expert Review Red