TNK2

Chr 3

tyrosine kinase non receptor 2

Also known as: ACK, ACK-1, ACK1, p21cdc42Hs

NCBI Gene: 10188 ENSG00000061938 UniProt: Q07912 OMIM: 606994

The protein is a non-receptor tyrosine kinase that regulates cell migration, survival, and proliferation through phosphorylation of multiple targets including AKT1 and plays roles in synaptic function and brain development. Mutations cause autosomal dominant developmental delays with or without dysmorphic facies and behavioral abnormalities. The gene is highly constrained against loss-of-function variants, suggesting intolerance to protein-disrupting mutations.

OMIM ResearchSummary from RefSeq, UniProt

This gene encodes a tyrosine kinase that binds Cdc42Hs in its GTP-bound form and inhibits both the intrinsic and GTPase-activating protein (GAP)-stimulated GTPase activity of Cdc42Hs. This binding is mediated by a unique sequence of 47 amino acids C-terminal to an SH3 domain. The protein may be involved in a regulatory mechanism that sustains the GTP-bound active form of Cdc42Hs and which is directly linked to a tyrosine phosphorylation signal transduction pathway. Several alternatively spliced transcript variants have been identified from this gene, but the full-length nature of only two transcript variants has been determined. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.80

Clinical Summary— TNK2

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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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ClinVar Variants

1 unique Pathogenic / Likely Pathogenic· 322 VUS of 525 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.80LOEUF

pLI 0.000

Z-score 2.61

OE 0.57 (0.42–0.80)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

-0.20Z-score

OE missense 1.02 (0.96–1.09)

710 obs / 695.0 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.57 (0.42–0.80)

0≤0.351.4

Missense OE?1.02 (0.96–1.09)

0≤0.61.4

Synonymous OE?1.36

0≤1.21.6

LoF obs/exp: 25 / 43.6Missense obs/exp: 710 / 695.0Syn Z: -4.89

This gene — mechanism propensity

0.7229th %ile

GOF

0.77top 25%

LOF

0.3358th %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.

ClinVar Variant Classifications

525 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic1

VUS322

Likely Benign118

Benign44

Conflicting10

Pathogenic

322

VUS

118

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	1	0	0	1
Likely Pathogenic	0	0	0	0	0
VUS	7	299	16	0	322
Likely Benign	1	13	29	75	118
Benign	0	8	7	29	44
Conflicting	—				10
Total	8	321	52	104	495

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

42 pathogenic / likely-pathogenic (of 61) ClinVar copy-number / structural variants overlap TNK2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →