TANC2

protein-coding

tetratricopeptide repeat, ankyrin repeat and coiled-coil containing 2, the group of Tetratricopeptide repeat domain containing|Ankyrin repeat domain containing

Gene summary

Predicted to be a structural constituent of postsynaptic density. Predicted to be involved in dense core granule cytoskeletal transport; regulation of dendritic spine development; and regulation of dendritic spine morphogenesis. Predicted to act upstream of or within in utero embryonic development. Located in dendritic spine. Implicated in intellectual developmental disorder with autistic features and language delay, with or without seizures. [provided by Alliance of Genome Resources, Jul 2025]

MANE transcript

NM_001394998.1

Inheritance

ClinVar variants

P:60U:532B:147

Top phenotype

Intellectual developmental disorder with autistic features and language delay, with or without seizures

gnomAD constraint

pLI —, LoF o/e 0.09

Max pathogenic AF

—

Genomic locus

chr17:62,966,235-63,427,703

External References & Databases

Ensembl (ENSG00000170921)

Transcript & Mutation Effects

hg38 • Region Span ~461.5 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

intellectual developmental disorder with autistic features and language delay, with or without seizuresSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0030051

Submitter: PanelApp Australia

intellectual developmental disorder with autistic features and language delay, with or without seizuresSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0030051

Submitter: Labcorp Genetics (formerly Invitae)

intellectual developmental disorder with autistic features and language delay, with or without seizuresSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0030051

Submitter: Illumina

intellectual developmental disorder with autistic features and language delay, with or without seizuresLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0030051

Submitter: G2P

intellectual developmental disorder with autistic features and language delay, with or without seizuresDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0030051

Submitter: ClinGen

*TANC2* encodes a synaptic scaffolding protein that interacts with multiple postsynaptic density proteins in dendrites. *TANC2* was first reported in relation to autosomal dominant intellectual developmental disorder with autistic features and language delay, with or without seizures in 2019 (Guo et al., PMID: 31616000). Pediatric patients present with delayed language and motor development, intellectual disability, autism, and variable epilepsy and facial dysmorphic features. Psychiatric disorders and behavioral problems were common in adult probands or carrier parents. Twenty-one loss-of-function variants (frameshift, nonsense, splice, and exon deletion) that have been reported in 22 probands in 4 publications (PMIDs: 31616000, 33160097, 34861844, 40110879) are included in this curation. Most variants occurred *de novo*, but some individuals inherited the variant from an affected parent. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. *De novo* missense variants in *TANC2* have been observed in individuals with neurodevelopmental disorders (PMIDs: 31616000, 40110879); however, these variants were not scored due to lack of experimental evidence of gene impact. *TANC2* is highly constrained for truncating variants (pLI = 1, LOEUF = 0.17, gnomAD v4.1.1) and also exhibits constraint for missense variants (Z score = 4.01). The mechanism of pathogenicity is haploinsufficiency. This gene-disease relationship is also supported by experimental evidence, including a mouse model, protein interactions, and *in vitro* functional assays. In summary, there is definitive evidence supporting the relationship between *TANC2* and autosomal dominant intellectual developmental disorder with autistic features and language delay, with or without seizures. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This gene-disease pair was originally evaluated by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on September 7, 2022. It was reevaluated on June 22, 2026 (SOP Version 12). Although additional cases were added, the classification did not change.

syndromic intellectual disabilitySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0000508

Submitter: Orphanet

intellectual developmental disorder with autistic features and language delay, with or without seizuresMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0030051

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Intellectual developmental disorder with autistic features and language delay, with or without seizuresAD

Manifestation: Craniofacial; Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 23033978; 24463507; 31616000

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TANC2 variants in ClinVar

19 Conditions Cataloged

not providedTotal: 389

Inborn genetic diseasesTotal: 239

Intellectual developmental disorder with autistic features and language delay, with or without seizuresTotal: 110

TANC2-related disorderTotal: 65

not specifiedTotal: 39

Autism spectrum disorderTotal: 10

Neurodevelopmental disorderTotal: 6

See casesTotal: 6

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001394998.1. 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	11 clinvar	82 clinvar	4 clinvar	98
missense		1 clinvar	503 clinvar	60 clinvar	1 clinvar	565
nonsense	10 clinvar	10 clinvar	5 clinvar			25
start loss			1 clinvar			1
frameshift	7 clinvar	17 clinvar	7 clinvar			31
splice donor/acceptor (+/-2bp)	5 clinvar	9 clinvar	5 clinvar			19
Total	22	38	532	142	5	739

Highest pathogenic variant AF is 0.0000037300535

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 32 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001394998.1	RefSeq	NP_001381927.1	27	MANE Select
ENST00000689528.1	Ensembl	ENSP00000510600.1	27	MANE Select
NM_001411076.1	RefSeq	NP_001398005.1	26	Standard
NM_025185.4	RefSeq	NP_079461.2	25	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

in utero embryonic development

Cellular Component

glutamatergic synapse
postsynaptic density, intracellular component

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000424789
Coding exons: 25
Length: 418144
Individuals with no LoFs: 124628
Homozygous LoFs: 0
Heterozygous LoFs: 15
Defined: 124643
p: 0.0000602

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.34	900	1.12e+3	0.803	0.0000648	12872
Missense (PolyPhen)		179	314.61	0.56895		3540
Synonymous	0.864	400	423	0.947	0.0000244	4060
Loss of Function	8.09	8	91.5	0.0874	0.00000548	1002

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00013	0.00013	rare
Latino/Admixed American	0.000030	0.000029	rare
Ashkenazi Jewish	0.00011	0.000099	rare
East Asian	0.000056	0.000056	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000082	0.000080	rare
South Asian	0.000033	0.000033	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Disease: DISEASE: Note=Defects in TANC2 has been found in a patient with isolated coloboma, a defect of the eye characterized by the absence of ocular structures due to abnormal morphogenesis of the optic cup and stalk, and the fusion of the fetal fissure (optic fissure). Isolated colobomas may be associated with an abnormally small eye (microphthalmia) or small cornea. {ECO:0000269|PubMed:28493397}.;

Recessive Scores

pRec: 0.114

Intolerance Scores

LoFtool: 0.262
RVIS EVS: -2.78
RVIS percentile EVS: 0.67

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.219

Gene Damage Prediction

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