TBCK

Summary

TBCK (TBC1 domain containing kinase, HGNC:28261) is a protein-coding gene on chromosome 4q24, encoding TBC domain-containing protein kinase-like protein (Q8TEA7). Component of the FERRY complex (Five-subunit Endosomal Rab5 and RNA/ribosome intermediary).

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.

Source: NCBI Gene 93627 — RefSeq curated summary.

At a glance

• Gene–disease (curated): syndromic complex neurodevelopmental disorder (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 9
• Clinical variants (ClinVar): 958 total — 64 pathogenic, 37 likely-pathogenic
• Phenotypes (HPO): 148
• MANE Select transcript: NM_001163435

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:28261
Approved symbol	TBCK
Name	TBC1 domain containing kinase
Location	4q24
Locus type	gene with protein product
Status	Approved
Aliases	MGC16169, HSPC302, Fy-1, FERRY1
Ensembl gene	ENSG00000145348
Ensembl biotype	protein_coding
OMIM	616899
Entrez	93627

Gene structure

Transcript identifiers

Ensembl transcripts: 30 — 19 protein_coding, 6 protein_coding_CDS_not_defined, 4 nonsense_mediated_decay, 1 retained_intron

ENST00000273980, ENST00000361687, ENST00000394706, ENST00000394708, ENST00000467183, ENST00000503516, ENST00000503832, ENST00000505574, ENST00000506280, ENST00000506384, ENST00000506615, ENST00000507696, ENST00000508666, ENST00000509532, ENST00000509862, ENST00000510927, ENST00000511011, ENST00000514689, ENST00000515705, ENST00000885937, ENST00000885938, ENST00000885939, ENST00000885940, ENST00000885941, ENST00000923624, ENST00000923625, ENST00000967907, ENST00000967908, ENST00000967909, ENST00000967910

RefSeq mRNA: 5 — MANE Select: NM_001163435 NM_001163435, NM_001163436, NM_001163437, NM_001290768, NM_033115

CCDS: CCDS3673, CCDS54788, CCDS54789

Canonical transcript exons

ENST00000394708 — 26 exons

Exon	Start	End
ENSE00001519301	106315931	106316209
ENSE00002069717	106041599	106046680
ENSE00002230940	106308768	106308989
ENSE00003466128	106262098	106262212
ENSE00003470257	106194718	106194754
ENSE00003473382	106251866	106252007
ENSE00003475765	106236759	106236808
ENSE00003481635	106212750	106212835
ENSE00003488173	106250418	106250478
ENSE00003513447	106116203	106116378
ENSE00003513895	106233588	106233650
ENSE00003550120	106244626	106244764
ENSE00003550630	106295094	106295166
ENSE00003572990	106171095	106171270
ENSE00003586753	106248921	106248982
ENSE00003589890	106236390	106236519
ENSE00003599915	106242470	106242569
ENSE00003602691	106247139	106247287
ENSE00003605870	106235269	106235367
ENSE00003611277	106095482	106095641
ENSE00003616441	106231729	106231779
ENSE00003628028	106248245	106248306
ENSE00003637958	106232938	106233064
ENSE00003653250	106193609	106193770
ENSE00003656446	106260437	106260510
ENSE00003679700	106230363	106230446

Expression profiles

Bgee: expression breadth ubiquitous, 258 present calls, max score 95.59.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 8.8070 / max 105.4209, expressed in 1741 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
53481	5.0321	1600
53482	3.5013	1438
53480	0.2480	96
53477	0.0153	4
53479	0.0103	4

Top tissues by expression

260 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
calcaneal tendon	UBERON:0003701	95.59	gold quality
kidney epithelium	UBERON:0004819	95.59	gold quality
adrenal tissue	UBERON:0018303	94.94	gold quality
pancreatic ductal cell	CL:0002079	93.82	gold quality
germinal epithelium of ovary	UBERON:0001304	92.76	gold quality
corpus callosum	UBERON:0002336	92.63	gold quality
sperm	CL:0000019	92.60	gold quality
cardiac muscle of right atrium	UBERON:0003379	92.04	gold quality
endometrium	UBERON:0001295	92.02	gold quality
corpus epididymis	UBERON:0004359	91.21	gold quality
renal medulla	UBERON:0000362	90.41	gold quality
thymus	UBERON:0002370	90.14	gold quality
pericardium	UBERON:0002407	89.80	gold quality
gingival epithelium	UBERON:0001949	89.65	gold quality
superficial temporal artery	UBERON:0001614	89.62	gold quality
mucosa of paranasal sinus	UBERON:0005030	89.43	gold quality
bone marrow cell	CL:0002092	89.25	gold quality
epithelium of mammary gland	UBERON:0003244	89.08	gold quality
mammary duct	UBERON:0001765	89.03	gold quality
ileal mucosa	UBERON:0000331	89.02	gold quality
gingiva	UBERON:0001828	88.95	gold quality
epithelial cell of pancreas	CL:0000083	88.88	gold quality
seminal vesicle	UBERON:0000998	88.87	gold quality
uterus	UBERON:0000995	88.74	gold quality
tibia	UBERON:0000979	88.62	gold quality
left ventricle myocardium	UBERON:0006566	88.58	gold quality
Brodmann (1909) area 23	UBERON:0013554	88.58	gold quality
gall bladder	UBERON:0002110	88.52	gold quality
colonic epithelium	UBERON:0000397	88.51	gold quality
metanephros	UBERON:0000081	88.50	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-GEOD-99795	no	58.08
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

153 targeting TBCK, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-3064-3P	100.00	70.09	1254
HSA-MIR-34A-5P	99.99	71.21	1784
HSA-MIR-449A	99.99	71.05	1776
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-6793-5P	99.97	65.95	758
HSA-MIR-34C-5P	99.97	70.45	1577
HSA-MIR-449B-5P	99.97	70.26	1580
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-545-3P	99.95	70.74	2783
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-23A-3P	99.95	74.24	3163
HSA-MIR-23B-3P	99.95	74.24	3163
HSA-MIR-23C	99.95	73.92	3192

Literature-anchored findings (GeneRIF, showing 15)

• TBCK may play an important role in cell proliferation, cell growth and actin organization possibly by modulating mTOR pathway. (PMID:23977024)
• localization and function of TBCK (PMID:24576458)
• We have reported a series of 13 individuals from nine unrelated families that harbor biallelic mutation in TBCK and display overlapping features of intellectual disability and hypotonia. This condition is called TBCK-related intellectual disability syndrome. (PMID:27040691)
• We have established that biallelic mutations in TBCK cause a severe neurodevelopmental disorder whose major features include profound developmental delay or cognitive deficit, brain atrophy without microcephaly. (PMID:27040692)
• RNAsequencing showed that the t(4;5)(q24;q31) resulted in recombination of the genes TBCK on 4q24 and P4HA2 on 5q31.1 with generation of an inframe TBCKP4HA2 and the reciprocal but outofframe P4HA2TBCK fusion transcripts. (PMID:27633981)
• We conclude that the c.1854delT variant in the TBCK gene is the mutation causing the congenital brain abnormality in an Arab-Moslem family from northern Israel. (PMID:27748029)
• TBCK-encephaloneuronopathy is a clinically distinguishable syndrome with progressive central and peripheral nervous system dysfunction, consistently observed in patients with the TBCK mutation (PMID:29283439)
• A novel TBCK mutation was identified in two siblings with infantile hypotonia, psychomotor retardation and characteristic facies type 3. (PMID:30103036)
• Evidence that TBC1 domain-containing kinase (TBCK) deficiency disorder associated with homozygous TBCK mutations is a novel type of lysosomal storage disease. (PMID:30591081)
• These findings suggest that miR-1208 acts as a tumor suppressor and targets TBCK directly, thus possessing great potential for use in renal cancer therapy. (PMID:31331056)
• A recurrent single-exon deletion in TBCK might be under-recognized in patients with infantile hypotonia and psychomotor delay. (PMID:36317458)
• Expanding the phenotype of children presenting with hypoventilation with biallelic TBCK pathogenic variants and literature review. (PMID:36522252)
• Heterozygous variants in TBCK cause a mild neurologic syndrome in humans and mice. (PMID:37353954)
• TBCK syndrome: a rare multi-organ neurodegenerative disease. (PMID:37455236)
• Mutation Of TBC1 Domain Containing Kinase (TBCK) With Associated Intellectual Disability And Hypotonia. (PMID:37876076)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	tbck	ENSDARG00000013667
mus_musculus	Tbck	ENSMUSG00000028030
rattus_norvegicus	Tbck	ENSRNOG00000011454
drosophila_melanogaster	CG4041	FBGN0029736
caenorhabditis_elegans		WBGENE00016352

Paralogs (45): RABGAP1 (ENSG00000011454), TBC1D22A (ENSG00000054611), TBC1D22B (ENSG00000065491), TBC1D1 (ENSG00000065882), EVI5 (ENSG00000067208), TBC1D25 (ENSG00000068354), TBC1D2 (ENSG00000095383), TBC1D10A (ENSG00000099992), SGSM3 (ENSG00000100359), TBC1D17 (ENSG00000104946), TBC1D13 (ENSG00000107021), TBC1D12 (ENSG00000108239), TBC1D9 (ENSG00000109436), TBC1D30 (ENSG00000111490), TBC1D15 (ENSG00000121749), TBC1D5 (ENSG00000131374), TBC1D14 (ENSG00000132405), TBC1D8B (ENSG00000133138), TBC1D4 (ENSG00000136111), GRTP1 (ENSG00000139835), SGSM2 (ENSG00000141258), EVI5L (ENSG00000142459), USP6NL (ENSG00000148429), RABGAP1L (ENSG00000152061), SGSM1 (ENSG00000167037), TBC1D21 (ENSG00000167139), TBC1D2B (ENSG00000167202), TBC1D16 (ENSG00000167291), TBC1D10B (ENSG00000169221), TBC1D10C (ENSG00000175463), TBC1D28 (ENSG00000189375), TBC1D9B (ENSG00000197226), TBC1D8 (ENSG00000204634), TBC1D26 (ENSG00000214946), TBC1D3G (ENSG00000260287), TBC1D3K (ENSG00000273513), TBC1D3H (ENSG00000274226), TBC1D3D (ENSG00000274419), TBC1D3L (ENSG00000274512), TBC1D3 (ENSG00000274611)

Protein

Protein identifiers

TBC domain-containing protein kinase-like protein — Q8TEA7 (reviewed: Q8TEA7)

Alternative names: FERRY endosomal RAB5 effector complex subunit 1

All UniProt accessions (9): Q8TEA7, D6R950, D6RC61, D6RDG2, D6RDY5, H0Y8U7, H0Y959, H0YA45, Q5HYF5

UniProt curated annotations — full annotation on UniProt →

Function. Component of the FERRY complex (Five-subunit Endosomal Rab5 and RNA/ribosome intermediary). The FERRY complex directly interacts with mRNAs and RAB5A, and functions as a RAB5A effector involved in the localization and the distribution of specific mRNAs most likely by mediating their endosomal transport. The complex recruits mRNAs and ribosomes to early endosomes through direct mRNA-interaction. Also involved in the modulation of mTOR signaling and expression of mTOR complex components. Involved in the control of actin-cytoskeleton organization.

Subunit / interactions. Component of the FERRY complex composed of five subunits, TBCK, PPP1R21, FERRY3, CRYZL1 and GATD1 with a ratio of 1:2:1:2:4, respectively.

Subcellular location. Cytoplasm. Cytoskeleton. Spindle. Midbody. Early endosome.

Disease relevance. 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. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The protein kinase domain is predicted to be catalytically inactive.

Similarity. Belongs to the protein kinase superfamily.

Isoforms (3)

UniProt ID	Names	Canonical?
Q8TEA7-1	1	yes
Q8TEA7-2	2
Q8TEA7-3	3

RefSeq proteins (5): NP_001156907, NP_001156908, NP_001156909, NP_001277697, NP_149106 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000195	Rab-GAP-TBC_dom	Domain
IPR000719	Prot_kinase_dom	Domain
IPR001763	Rhodanese-like_dom	Domain
IPR011009	Kinase-like_dom_sf	Homologous_superfamily
IPR035969	Rab-GAP_TBC_sf	Homologous_superfamily
IPR036873	Rhodanese-like_dom_sf	Homologous_superfamily

Pfam: PF00069, PF00566, PF00581

UniProt features (21 total): sequence variant 12, domain 3, splice variant 2, chain 1, sequence conflict 1, region of interest 1, compositionally biased region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8TEA7-F1	87.42	0.66

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 432 (showing top): GCM_MAP4K4, chr4q24, GCM_GSPT1, GGGTGGRR_PAX4_03, MOLENAAR_TARGETS_OF_CCND1_AND_CDK4_UP, GCM_SUFU, GOBP_TOR_SIGNALING, GCM_NF2, ACEVEDO_LIVER_CANCER_UP, GOBP_RNA_LOCALIZATION, CHIANG_LIVER_CANCER_SUBCLASS_CTNNB1_UP, GOCC_SPINDLE, GOCC_MITOTIC_SPINDLE, GOCC_MIDBODY, GOMF_PROTEIN_KINASE_ACTIVITY

GO Biological Process (4): cell population proliferation (GO:0008283), actin cytoskeleton organization (GO:0030036), regulation of TOR signaling (GO:0032006), protein phosphorylation (GO:0006468)

GO Molecular Function (4): protein kinase activity (GO:0004672), GTPase activator activity (GO:0005096), ATP binding (GO:0005524), protein binding (GO:0005515)

GO Cellular Component (7): cytoplasm (GO:0005737), early endosome (GO:0005769), midbody (GO:0030496), mitotic spindle (GO:0072686), endosome (GO:0005768), spindle (GO:0005819), cytoskeleton (GO:0005856)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
intracellular membraneless organelle	2
cellular process	1
cytoskeleton organization	1
actin filament-based process	1
TOR signaling	1
regulation of intracellular signal transduction	1
phosphorylation	1
protein modification process	1
kinase activity	1
phosphotransferase activity, alcohol group as acceptor	1
catalytic activity, acting on a protein	1
GTPase activity	1
enzyme activator activity	1
GTPase regulator activity	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
binding	1
intracellular anatomical structure	1
endosome	1
spindle	1
endomembrane system	1
cytoplasmic vesicle	1
microtubule cytoskeleton	1

Protein interactions and networks

STRING

806 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TBCK	FERRY3	Q9NQ89	715
TBCK	TBC1D23	Q9NUY8	522
TBCK	PPP1R21	Q6ZMI0	503
TBCK	TBC1D19	Q8N5T2	488
TBCK	TBC1D20	Q96BZ9	479
TBCK	TST	Q16762	478
TBCK	NME6	O75414	454
TBCK	TBC1D24	Q9ULP9	435
TBCK	SH3BGRL3	Q9H299	429
TBCK	CDC16	Q13042	427
TBCK	CLN3	Q13286	422
TBCK	USP6	P35125	419
TBCK	CLN5	O75503	404
TBCK	TBC1D7	Q9P0N9	402
TBCK	C9orf153	Q5TBE3	397
TBCK	WDR47	O94967	397

IntAct

16 interactions, top by confidence:

A	B	Type	Score
FERRY3	CRYZL1	psi-mi:“MI:0915”(physical association)	0.690
PPP1R21	TBCK	psi-mi:“MI:0407”(direct interaction)	0.590
TCP10L	CRYZL1	psi-mi:“MI:0914”(association)	0.530
TUSC2	HSPA8	psi-mi:“MI:0914”(association)	0.530
TBCK	COX4I1	psi-mi:“MI:0915”(physical association)	0.400
PPP1R21		psi-mi:“MI:0914”(association)	0.350
Prdm16	ESYT2	psi-mi:“MI:0914”(association)	0.350
TBCK	MYO1C	psi-mi:“MI:0914”(association)	0.350
RAB5A	CRYZL1	psi-mi:“MI:0914”(association)	0.350
FERRY3	GAPDHS	psi-mi:“MI:0914”(association)	0.350
IL6R	MID1	psi-mi:“MI:0914”(association)	0.350
TCP10L	RNF40	psi-mi:“MI:0914”(association)	0.350
RBPMS	CA2	psi-mi:“MI:0914”(association)	0.350

BioGRID (93): TBCK (Affinity Capture-MS), TBCK (Affinity Capture-MS), TBCK (Affinity Capture-MS), TBCK (Affinity Capture-MS), TBCK (Affinity Capture-RNA), TBCK (Affinity Capture-MS), TBCK (Proximity Label-MS), TBCK (Affinity Capture-MS), TBCK (Affinity Capture-MS), TBCK (Affinity Capture-MS), TBCK (Proximity Label-MS), TBCK (Negative Genetic), COG3 (Co-fractionation), MYO1C (Affinity Capture-MS), SPTBN2 (Affinity Capture-MS)

ESM2 similar proteins: A1KXW8, A6QL50, E1BGQ2, H0Y354, O94955, P47224, Q08326, Q0IIH8, Q1JQA1, Q1RMS8, Q1RMZ1, Q2TBU5, Q3T1H6, Q4R372, Q4R528, Q4R9C4, Q5F480, Q5F4A1, Q5I0G3, Q5RCQ0, Q5RFG8, Q5TFE4, Q5TYM5, Q641X7, Q6L9T8, Q6PIP5, Q7L622, Q7Z6J8, Q7ZX59, Q86X60, Q8BFZ8, Q8BKW4, Q8BM85, Q8BX13, Q8CEL2, Q8N5C7, Q8N635, Q8NHU2, Q8TCF1, Q8TCJ0

Diamond homologs: A4VHH7, A5VXJ2, B0KJ90, B8F6J5, C3K330, P0AG27, P0AG28, P0AG29, P44854, P54510, P57160, Q15ZU3, Q3IHW1, Q48NU0, Q4K4X2, Q4ZMG2, Q88QT9, Q8BM85, Q8TEA7, A0A194W8T8, A0A194WDG1, A4L9P5, A8XSC1, B0XXN8, B0Y4X4, E9PSL7, F1NBT0, F4HQ17, G4N374, O01775, O13352, O14578, O44514, O55076, O61847, O76039, O88866, O88904, P06493, P11440

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
TBCK	“up-regulates activity”	mTORC1
TBCK	up-regulates	Proliferation
TBCK	up-regulates	Actin_cytoskeleton_reorganization

Disease & clinical

Clinical variants and AI predictions

ClinVar

958 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	64
Likely pathogenic	37
Uncertain significance	363
Likely benign	361
Benign	70

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1068725	NC_000004.11:g.(?107092232)(107092447_?)del	Pathogenic
1176804	GRCh37/hg19 4q24(chr4:107092252-107092427)x1	Pathogenic
1325175	NM_001163435.3(TBCK):c.1290del (p.Arg431fs)	Pathogenic
1327511	NM_001163435.3(TBCK):c.2060_2235del (p.Glu687fs)	Pathogenic
1327512	NM_001163435.3(TBCK):c.2130C>G (p.Tyr710Ter)	Pathogenic
1357150	NM_001163435.3(TBCK):c.827del (p.Val276fs)	Pathogenic
1419467	NC_000004.11:g.(?107151500)(107154827_?)del	Pathogenic
1451785	NM_001163435.3(TBCK):c.1250del (p.Asn417fs)	Pathogenic
1452987	NM_001163435.3(TBCK):c.1605G>A (p.Trp535Ter)	Pathogenic
1455366	NC_000004.11:g.(?107170058)(107183389_?)del	Pathogenic
1675955	NM_001163435.3(TBCK):c.1786_1787del (p.Val596fs)	Pathogenic
183338	NM_001163435.3(TBCK):c.1897+1G>A	Pathogenic
2018585	NM_001163435.3(TBCK):c.1378del (p.Trp460fs)	Pathogenic
2021195	NM_033115.5(TBCK):c.267-8502del	Pathogenic
2047227	NM_001163435.3(TBCK):c.1439del (p.Leu480fs)	Pathogenic
2115364	NM_001163435.3(TBCK):c.1372C>T (p.Gln458Ter)	Pathogenic
2128154	NM_001163435.3(TBCK):c.1938del (p.Leu647fs)	Pathogenic
225235	NM_001163435.3(TBCK):c.376C>T (p.Arg126Ter)	Pathogenic
225236	NM_001163435.3(TBCK):c.1363A>T (p.Lys455Ter)	Pathogenic
225238	NM_001163435.3(TBCK):c.831_832insTA (p.Pro278fs)	Pathogenic
225240	NM_001163435.3(TBCK):c.803_806del (p.Met268fs)	Pathogenic
225241	NM_001163435.3(TBCK):c.1370del (p.Asn457fs)	Pathogenic
2423895	NC_000004.11:g.(?107216231)(107230117_?)del	Pathogenic
2423896	NC_000004.11:g.(?107114746)(107115931_?)del	Pathogenic
2423897	NC_000004.11:g.(?107114746)(107171655_?)del	Pathogenic
2579177	GRCh38/hg38 4q24(chr4:106170998-106171368)x0	Pathogenic
2708673	NM_001163435.3(TBCK):c.1203C>A (p.Tyr401Ter)	Pathogenic
2866281	NM_001163435.3(TBCK):c.253del (p.Arg85fs)	Pathogenic
2909689	NM_001163435.3(TBCK):c.1334del (p.Phe445fs)	Pathogenic
3233781	NC_000004.11:g.(107169464_107170077)_(107183370_107216250)del	Pathogenic

SpliceAI

5814 predictions. Top by Δscore:

Variant	Effect	Δscore
4:106095480:A:AC	donor_gain	1.0000
4:106095481:C:CC	donor_gain	1.0000
4:106095481:CCT:C	donor_gain	1.0000
4:106116174:C:A	donor_gain	1.0000
4:106116201:A:AC	donor_gain	1.0000
4:106116202:C:CC	donor_gain	1.0000
4:106116202:CT:C	donor_gain	1.0000
4:106116202:CTCT:C	donor_gain	1.0000
4:106116203:TCTT:T	donor_gain	1.0000
4:106116204:CTTC:C	donor_gain	1.0000
4:106116225:C:CT	donor_gain	1.0000
4:106116226:C:CT	donor_gain	1.0000
4:106116374:CTTGA:C	acceptor_gain	1.0000
4:106116375:TTGA:T	acceptor_gain	1.0000
4:106116376:TGA:T	acceptor_gain	1.0000
4:106116377:GA:G	acceptor_gain	1.0000
4:106116377:GACT:G	acceptor_loss	1.0000
4:106116379:C:CC	acceptor_gain	1.0000
4:106116379:CTGAA:C	acceptor_loss	1.0000
4:106116393:G:C	acceptor_gain	1.0000
4:106171090:CATA:C	donor_loss	1.0000
4:106171091:ATACC:A	donor_loss	1.0000
4:106171092:TAC:T	donor_loss	1.0000
4:106171093:ACC:A	donor_loss	1.0000
4:106171281:A:C	acceptor_gain	1.0000
4:106171286:T:TC	acceptor_gain	1.0000
4:106193768:CAT:C	acceptor_gain	1.0000
4:106212749:CAT:C	donor_gain	1.0000
4:106230442:CAAGG:C	acceptor_gain	1.0000
4:106233063:ATCT:A	acceptor_loss	1.0000

AlphaMissense

5878 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:106193629:A:G	L680P	1.000
4:106193632:A:C	I679S	1.000
4:106193632:A:G	I679T	1.000
4:106193632:A:T	I679N	1.000
4:106193634:A:C	C678W	1.000
4:106193643:A:C	F675L	1.000
4:106193643:A:T	F675L	1.000
4:106193644:A:C	F675C	1.000
4:106193645:A:G	F675L	1.000
4:106193659:A:G	L670P	1.000
4:106193680:A:G	L663P	1.000
4:106193692:C:T	G659E	1.000
4:106193693:C:G	G659R	1.000
4:106193693:C:T	G659R	1.000
4:106193734:T:A	D645V	1.000
4:106193734:T:G	D645A	1.000
4:106193735:C:G	D645H	1.000
4:106193738:A:G	W644R	1.000
4:106193738:A:T	W644R	1.000
4:106193740:A:G	L643P	1.000
4:106194729:G:A	T629I	1.000
4:106194732:A:G	L628P	1.000
4:106194732:A:T	L628H	1.000
4:106194737:C:A	W626C	1.000
4:106194737:C:G	W626C	1.000
4:106194739:A:G	W626R	1.000
4:106194739:A:T	W626R	1.000
4:106194741:G:T	P625H	1.000
4:106194744:A:T	I624N	1.000
4:106194747:G:T	A623D	1.000

dbSNP variants (sampled 300 via entrez): RS10000428 (4:106175551 A>C,G,T), RS1000044866 (4:106157969 C>T), RS1000048721 (4:106180177 C>G,T), RS1000052316 (4:106308629 T>G), RS10000736 (4:106044741 A>G), RS1000074372 (4:106237349 A>G), RS1000083789 (4:106248110 G>A), RS1000096360 (4:106243107 C>T), RS1000096572 (4:106150344 T>C), RS1000117120 (4:106063625 C>A,T), RS1000147261 (4:106082138 C>T), RS1000156901 (4:106280363 T>C), RS1000159438 (4:106223773 C>G), RS1000163856 (4:106101679 G>A), RS1000172344 (4:106133491 A>G)

Disease associations

OMIM: gene MIM:616899 | disease phenotypes: MIM:616900, MIM:615419

GenCC curated gene-disease

Disease	Classification	Inheritance
hypotonia, infantile, with psychomotor retardation and characteristic facies 3	Definitive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
syndromic complex neurodevelopmental disorder	Definitive	AR

Mondo (5): hypotonia, infantile, with psychomotor retardation and characteristic facies 3 (MONDO:0014823), congenital nervous system disorder (MONDO:0002320), hypotonia, infantile, with psychomotor retardation and characteristic facies 1 (MONDO:0024567), neurodevelopmental disorder (MONDO:0700092), intellectual disability (MONDO:0001071)

Orphanet (4): TBCK-related encephalopathy-severe hypotonia-craniofacial dysmorphism syndrome (Orphanet:488632), Hypotonia-speech impairment-severe cognitive delay syndrome (Orphanet:371364), Hypotonia-speech impairment-severe cognitive delay syndrome due to NALCN deficiency (Orphanet:700336), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

148 total (30 of 148 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000011	Neurogenic bladder
HP:0000028	Cryptorchidism
HP:0000158	Macroglossia
HP:0000194	Open mouth
HP:0000212	Gingival overgrowth
HP:0000218	High palate
HP:0000238	Hydrocephalus
HP:0000248	Brachycephaly
HP:0000252	Microcephaly
HP:0000256	Macrocephaly
HP:0000262	Turricephaly
HP:0000280	Coarse facial features
HP:0000286	Epicanthus
HP:0000303	Mandibular prognathia
HP:0000316	Hypertelorism
HP:0000337	Broad forehead
HP:0000340	Sloping forehead
HP:0000341	Narrow forehead
HP:0000343	Long philtrum
HP:0000347	Micrognathia
HP:0000365	Hearing impairment
HP:0000369	Low-set ears
HP:0000407	Sensorineural hearing impairment
HP:0000414	Bulbous nose
HP:0000426	Prominent nasal bridge
HP:0000431	Wide nasal bridge
HP:0000463	Anteverted nares
HP:0000470	Short neck
HP:0000486	Strabismus

GWAS associations

9 associations (top):

Study	Trait	p-value
GCST001621_28	Airflow obstruction	6.000000e-06
GCST003542_180	Night sleep phenotypes	4.000000e-06
GCST004776_35	Systolic blood pressure	3.000000e-16
GCST004776_85	Systolic blood pressure	1.000000e-08
GCST007094_85	Diastolic blood pressure	3.000000e-08
GCST007096_187	Pulse pressure	4.000000e-06
GCST007099_243	Systolic blood pressure	2.000000e-11
GCST009391_88	Metabolite levels	8.000000e-06
GCST009798_66	Asthma	4.000000e-09

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0003892	pulmonary function measurement
EFO:0006335	systolic blood pressure
EFO:0006336	diastolic blood pressure
EFO:0005763	pulse pressure measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D065886	Neurodevelopmental Disorders	F03.625

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — TBCK family

CTD chemical–gene interactions

29 total (human), top 29 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression	2
Air Pollutants	decreases expression, increases abundance	2
Benzo(a)pyrene	decreases expression	2
GSK-J4	increases expression	1
FR900359	increases phosphorylation	1
bisphenol F	affects cotreatment, increases methylation	1
TAK-243	decreases sumoylation	1
methylmercuric chloride	decreases expression	1
triphenyl phosphate	affects expression	1
butyraldehyde	decreases expression	1
potassium chromate(VI)	decreases expression	1
chromium hexavalent ion	decreases expression	1
ICG 001	decreases expression	1
Sunitinib	decreases expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Acetaminophen	decreases expression	1
Arsenic	affects methylation	1
Atrazine	decreases expression	1
Benzene	decreases expression	1
Doxorubicin	decreases expression	1
Formaldehyde	decreases expression	1
Quercetin	decreases expression	1
Rotenone	decreases expression	1
Silicon Dioxide	decreases expression	1
Tobacco Smoke Pollution	decreases expression	1
Vanadates	increases expression	1
Okadaic Acid	decreases expression	1
Copper Sulfate	decreases expression	1
Particulate Matter	decreases expression, increases abundance	1

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_TR71	HAP1 TBCK (-)	Cancer cell line	Male

Clinical trials (associated diseases)

299 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT04586348	PHASE4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	PHASE4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT02559102	PHASE3	COMPLETED	Dexmedetomidine Sedation Versus General Anaesthesia for Inguinal Hernia Surgery in Infants
NCT02757079	PHASE3	COMPLETED	Study of the Efficacy and Safety of NPC-15 for Sleep Disorders of Children With Neurodevelopmental Disorders
NCT06915480	PHASE3	RECRUITING	Reducing Missed Appointments
NCT07377032	PHASE3	RECRUITING	TAP-GRIN: Interventional Study on Patients With GRIN-related Neurodevelopmental Disorders
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT02909959	PHASE2	COMPLETED	Sulforaphane for the Treatment of Young Men With Autism Spectrum Disorder
NCT06081348	PHASE2	RECRUITING	Sertraline vs. Placebo in the Treatment of Anxiety in Children and AdoLescents With NeurodevelopMental Disorders
NCT06352372	PHASE2	COMPLETED	Safety and Efficacy of tPBM for Epileptiform Activity in Autism
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT00503191	PHASE1	COMPLETED	NeuroModulation Technique Treatment of Autism
NCT04475848	PHASE1	COMPLETED	A Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Food Effect of RO6953958 in Healthy Participants
NCT06300398	PHASE1	COMPLETED	IAMA-6 Oral Dose Study in Healthy Adults
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	PHASE1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
NCT01783041	PHASE2/PHASE3	COMPLETED	Effect of Early L-Carnitine Supplementation on Neurodevelopmental Outcomes in Very Preterm Infants
NCT05767385	PHASE2/PHASE3	RECRUITING	Fetal Cerebrovascular Autoregulation in Congenital Heart Disease and Association With Neonatal Neurobehavior
NCT05675098	EARLY_PHASE1	NOT_YET_RECRUITING	Central Nervous System Stimulants and Physical Function in Children With Cerebral Palsy
NCT00783783	Not specified	COMPLETED	CYP2D6 Pharmacogenetics in Risperidone-Treated Children
NCT01778504	Not specified	RECRUITING	Studying Childhood-onset Behavioral, Psychiatric, and Developmental Disorders
NCT01850784	Not specified	UNKNOWN	High Energy Formula Feeding in Infants With Congenital Heart Disease
NCT01922791	Not specified	COMPLETED	Nutrition and Pregnancy Intervention Study
NCT01942525	Not specified	UNKNOWN	Influence of Intrauterine Growth Restriction on Amplitude-integrated EEG in Preterm Infants
NCT02003170	Not specified	COMPLETED	Etiology and Early Diagnosis of Neurodevelopmental Disorders
NCT02118649	Not specified	ACTIVE_NOT_RECRUITING	Enhancing Behavior and Brain Response to Visual Targets Using a Computer Game
NCT02557191	Not specified	TERMINATED	Biomarkers, Neurodevelopment and Preterm Infants
NCT02690675	Not specified	COMPLETED	Iron Supplement Effect on Child Development
NCT02694003	Not specified	COMPLETED	Better Nights, Better Days for Children With Neurodevelopment Disorders
NCT02792894	Not specified	COMPLETED	Family Networks (FaNs) for Children With Developmental Disorders and Delays