TTBK2

Chr 15AD

tau tubulin kinase 2

Also known as: SCA11, TTBK

NCBI Gene: 146057 ENSG00000128881 UniProt: Q6IQ55 OMIM: 611695

This serine/threonine kinase regulates ciliogenesis by controlling the initiation of primary cilia formation and phosphorylates tau protein. Mutations cause spinocerebellar ataxia 11, a progressive neurodegenerative disorder characterized by ataxia and cerebellar-brainstem atrophy, inherited in an autosomal dominant pattern. The gene is highly constrained against loss-of-function variants, indicating intolerance to protein-truncating mutations.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a serine-threonine kinase that putatively phosphorylates tau and tubulin proteins. Mutations in this gene cause spinocerebellar ataxia type 11 (SCA11); a neurodegenerative disease characterized by progressive ataxia and atrophy of the cerebellum and brainstem. [provided by RefSeq, Aug 2009]

OMIM ResearchGenerating clinical summary…

MultiplemechanismADLOEUF 0.261 OMIM phenotype

Clinical Summary— TTBK2

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.26LOEUF

pLI 0.999

Z-score 5.66

OE 0.14 (0.08–0.26)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

1.39Z-score

OE missense 0.85 (0.79–0.91)

558 obs / 658.5 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.14 (0.08–0.26)

0≤0.351.4

Missense OE?0.85 (0.79–0.91)

0≤0.61.4

Synonymous OE?0.99

0≤1.21.6

LoF obs/exp: 7 / 50.3Missense obs/exp: 558 / 658.5Syn Z: 0.10

This gene — mechanism propensity

0.4289th %ile

GOF

0.5269th %ile

LOF

0.73top 10%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to loss-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFprediction above median · LOEUF 0.26

DN1 literature citation

Literature Evidence

DNIn this work, we present evidence that SCA11-associated mutations are dominant negative alleles and that the resulting truncated protein (TTBK2SCA11) interferes with the function of full length TTBK2 in mediating ciliogenesis.1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References