TBCK

Chr 4AR

TBC1 domain containing kinase

Also known as: FERRY1, Fy-1, HSPC302, IHPRF3, TBCKL

NCBI Gene: 93627 ENSG00000145348 UniProt: Q8TEA7 OMIM: 616899

The protein contains a kinase domain and regulates mTOR signaling pathway to control actin organization, cell growth, and cell proliferation. Biallelic mutations cause hypotonia, infantile, with psychomotor retardation and characteristic facies 3, inherited in an autosomal recessive pattern. The pathogenic mechanism involves loss of function, disrupting normal mTOR-mediated cellular processes essential for neuronal development.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

This gene encodes a protein that contains a protein kinase domain, a Rhodanase-like domain and the Tre-2/Bub2/Cdc16 (TBC) domain. The encoded protein is thought to play a role in actin organization, cell growth and cell proliferation by regulating the mammalian target of the rapamycin (mTOR) signaling pathway. This protein may also be involved in the transcriptional regulation of the components of the mTOR complex. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2014]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 0.871 OMIM phenotype

Clinical Summary— TBCK

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Gene-Disease Validity (ClinGen)

syndromic complex neurodevelopmental disorder · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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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

118 unique Pathogenic / Likely Pathogenic· 363 VUS of 955 total submissions

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Clinical Trials

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

Explore recent and relevant literature in Research Assistant →

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GeneReview available — TBCK

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.87LOEUF

pLI 0.000

Z-score 2.28

OE 0.65 (0.48–0.87)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.50Z-score

OE missense 0.93 (0.86–1.01)

418 obs / 448.0 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.65 (0.48–0.87)

0≤0.351.4

Missense OE?0.93 (0.86–1.01)

0≤0.61.4

Synonymous OE?0.99

0≤1.21.6

LoF obs/exp: 31 / 48.0Missense obs/exp: 418 / 448.0Syn Z: 0.07

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveTBCK-related severe infantile syndromic encephalopathyLOFAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.6936th %ile

GOF

0.6540th %ile

LOF

0.2872th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

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

ClinVar Variant Classifications

955 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic58

Likely Pathogenic60

VUS363

Likely Benign364

Benign72

Conflicting16

Pathogenic

Likely Pathogenic

363

VUS

364

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	45	0	13	0	58
Likely Pathogenic	52	1	7	0	60
VUS	2	324	34	3	363
Likely Benign	0	9	189	166	364
Benign	0	5	60	7	72
Conflicting	—				16
Total	99	339	303	176	933

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

View in ClinVar →

21 pathogenic / likely-pathogenic (of 29) ClinVar copy-number / structural variants overlap TBCK — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →