TESK2

Chr 1

testis associated actin remodelling kinase 2

NCBI Gene: 10420 ENSG00000070759 UniProt: Q96S53 OMIM: 604746

This gene encodes a dual specificity protein kinase that phosphorylates cofilin and plays an important role in spermatogenesis, with predominant expression in testis and prostate. Mutations in TESK2 cause neurodevelopmental disorder with seizures and nonepileptic hyperkinetic movements, following an autosomal dominant inheritance pattern. The gene is not highly constrained against loss-of-function variants.

OMIM ResearchSummary from RefSeq, UniProt

This gene product is a serine/threonine protein kinase that contains an N-terminal protein kinase domain that is structurally similar to the kinase domains of testis-specific protein kinase-1 and the LIM motif-containing protein kinases (LIMKs). Its overall structure is most related to the former, indicating that it belongs to the TESK subgroup of the LIMK/TESK family of protein kinases. This gene is predominantly expressed in testis and prostate. The developmental expression pattern of the rat gene in testis suggests an important role for this gene in meitoic stages and/or early stages of spermiogenesis. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2016]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.81

Clinical Summary— TESK2

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.81LOEUF

pLI 0.000

Z-score 2.36

OE 0.52 (0.35–0.81)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.49Z-score

OE missense 0.92 (0.84–1.01)

318 obs / 343.8 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.52 (0.35–0.81)

0≤0.351.4

Missense OE?0.92 (0.84–1.01)

0≤0.61.4

Synonymous OE?1.01

0≤1.21.6

LoF obs/exp: 15 / 28.6Missense obs/exp: 318 / 343.8Syn Z: -0.10

This gene — mechanism propensity

0.7228th %ile

GOF

0.79top 25%

LOF

0.3550th %ile

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

GOFprediction above median

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.