TBCK

protein-coding

TBC1 domain containing kinase

Gene summary

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]

MANE transcript

NM_001163435.3

Inheritance

ClinVar variants

P:113U:341B:192

Top phenotype

Hypotonia, infantile, with psychomotor retardation and characteristic facies 3

gnomAD constraint

pLI —, LoF o/e 0.65

Max pathogenic AF

—

Genomic locus

chr4:106,041,599-106,316,683

External References & Databases

Ensembl (ENSG00000145348)

Transcript & Mutation Effects

hg38 • Region Span ~275.1 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

syndromic complex neurodevelopmental disorderDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0800439

Submitter: ClinGen

*TBCK* was first reported in relation to autosomal recessive syndromic complex neurodevelopmental disorder in 2016 (Bhoj et al., PMID: 27040691). There is marked clinical variability in patients, ranging from mild to severe. The severe phenotype is progressive, often leads to early death, and consists of prominent motor neuron degeneration, profound intellectual disability, leukoencephalopathy and brain atrophy, chronic respiratory failure, refractory epilepsy, and clinical features reminiscent of lysosomal storage disorders. The milder form is non-progressive, and presents with mild intellectual disability, autistic features, and mild motor impairment. The biological factors underlying this variable disease presentation remain unknown. Seven variants (nonsense, frameshift, and in-frame exonic deletion) reported in six probands from four publications (PMIDs: 27040691, 30591081, 35095425, 36317458) are included in this curation. Three variants are recurrent, including a founder variant known as the Boricua mutation in individuals of Puerto Rican descent (p.Arg126*) that is associated with the severe phenotype (PMIDs: 27040691, 27040692). More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. The mechanism of pathogenicity is known to be loss of function (PMIDs: 27040691, 27040692, 34816123, 35095425). *TBCK* encodes a putative GTPase-activating protein and has been shown to control cell growth and proliferation, actin cytoskeleton dynamics, and mTOR signaling. This gene-disease relationship is supported by findings in skin, lymphocytic, and neuroprogenitor cells from both mildly and severely affected individuals equally demonstrating reduced mRNA and protein expression and decreased mTOR signaling compared to controls (PMIDs: 27040691, 27040692, 35095425). Greater mitochondrial and lysosomal defects were observed in fibroblasts from individuals expressing the severe neurodegenerative phenotype compared to those with a milder phenotype (PMID: 29283439). Additionally, histopathological features of lysosomal storage disease were detected by autopsy in siblings affected with the more severe *TBCK* encephalopathy (PMID 34816123). In summary, there is definitive evidence supporting the relationship between *TBCK* and autosomal recessive syndromic complex neurodevelopmental disorder. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on February 7, 2024 (SOP Version 10).

hypotonia, infantile, with psychomotor retardation and characteristic facies 3STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014823

Submitter: PanelApp Australia

hypotonia, infantile, with psychomotor retardation and characteristic facies 3STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014823

Submitter: Labcorp Genetics (formerly Invitae)

hypotonia, infantile, with psychomotor retardation and characteristic facies 3DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014823

Submitter: G2P

Clinical Genomic Database (CGD)

Hypotonia, infantile, with psychomotor retardation and characteristic facies 3AR

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: 25558065; 27040691; 27040692

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TBCK variants in ClinVar

16 Conditions Cataloged

not providedTotal: 764

Inborn genetic diseasesTotal: 124

Hypotonia, infantile, with psychomotor retardation and characteristic facies 3Total: 112

TBCK-related disorderTotal: 47

not specifiedTotal: 46

Syndromic Infantile EncephalopathyTotal: 3

Global developmental delayTotal: 2

Hypotonia, infantile, with psychomotor retardation and characteristic facies 1Total: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001163435.3. 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			6 clinvar	172 clinvar	3 clinvar	181
missense		7 clinvar	328 clinvar	16 clinvar	1 clinvar	352
nonsense	13 clinvar	16 clinvar				29
start loss			1 clinvar			1
frameshift	23 clinvar	21 clinvar				44
splice donor/acceptor (+/-2bp)	10 clinvar	23 clinvar	6 clinvar			39
Total	46	67	341	188	4	646

Highest pathogenic variant AF is 0.00016439981

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 61 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001163435.3	RefSeq	NP_001156907.2	25	MANE Select
ENST00000394708.7	Ensembl	ENSP00000378198.2	25	MANE Select
NM_001163436.4	RefSeq	NP_001156908.2	25	Standard
NM_001163437.3	RefSeq	NP_001156909.2	25	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

protein phosphorylation
intracellular protein transport
cell population proliferation
actin cytoskeleton organization
regulation of TOR signaling

Molecular Function

protein kinase activity
GTPase activator activity
ATP binding
Rab GTPase binding

Cellular Component

cytoplasm
midbody
mitotic spindle

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000273980
Coding exons: 25
Length: 279897
Individuals with no LoFs: 125662
Homozygous LoFs: 0
Heterozygous LoFs: 86
Defined: 125748
p: 0.000342

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.503	418	448	0.933	0.0000221	5832
Missense (PolyPhen)		98	131.75	0.74383		1727
Synonymous	0.0750	161	162	0.993	0.00000820	1691
Loss of Function	2.28	31	48.0	0.645	0.00000249	638

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00025	0.00025	rare
Latino/Admixed American	0.00045	0.00043	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00029	0.00027	rare
Finnish	0.00014	0.00014	rare
European (Non-Finnish)	0.00045	0.00044	rare
South Asian	0.00027	0.00026	rare
Other	0.00018	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Involved in the modulation of mTOR signaling and expression of mTOR complex components (PubMed:27040691, PubMed:23977024). Involved in the regulation of cell proliferation and growth (PubMed:23977024, PubMed:24576458). Involved in the control of actin-cytoskeleton organization (PubMed:23977024). {ECO:0000269|PubMed:23977024, ECO:0000269|PubMed:24576458, ECO:0000269|PubMed:27040691}.;
Disease: DISEASE: Hypotonia, infantile, with psychomotor retardation and characteristic facies 3 (IHPRF3) [MIM:616900]: An autosomal recessive neurodevelopmental disorder characterized by profound developmental disability, intellectual disability and severe hypotonia. Many patients have seizures, and show brain atrophy, dysgenesis of the corpus callosum and white-matter changes on neuroimaging. Non-specific facial dysmorphism is noted in some individuals. {ECO:0000269|PubMed:25558065, ECO:0000269|PubMed:27040691, ECO:0000269|PubMed:27040692}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Intolerance Scores

RVIS EVS: -0.04
RVIS percentile EVS: 50.5

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.114

Gene Damage Prediction

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