RHOBTB2

Summary

RHOBTB2 (Rho related BTB domain containing 2, HGNC:18756) is a protein-coding gene on chromosome 8p21.3, encoding Rho-related BTB domain-containing protein 2 (Q9BYZ6). Regulator of cell proliferation and apoptosis.

The protein encoded by this gene is a small Rho GTPase and a candidate tumor suppressor. The encoded protein interacts with the cullin-3 protein, a ubiquitin E3 ligase necessary for mitotic cell division. This protein inhibits the growth and spread of some types of breast cancer. Three transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 23221 — RefSeq curated summary.

At a glance

• Gene–disease (curated): complex neurodevelopmental disorder (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 8
• Clinical variants (ClinVar): 830 total — 4 pathogenic, 6 likely-pathogenic
• Phenotypes (HPO): 149
• MANE Select transcript: NM_015178

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:18756
Approved symbol	RHOBTB2
Name	Rho related BTB domain containing 2
Location	8p21.3
Locus type	gene with protein product
Status	Approved
Aliases	KIAA0717, DBC2
Ensembl gene	ENSG00000008853
Ensembl biotype	protein_coding
OMIM	607352
Entrez	23221

Gene structure

Transcript identifiers

Ensembl transcripts: 18 — 13 protein_coding, 3 retained_intron, 2 protein_coding_CDS_not_defined

ENST00000251822, ENST00000517528, ENST00000518534, ENST00000519210, ENST00000519685, ENST00000522948, ENST00000523918, ENST00000524077, ENST00000690180, ENST00000692529, ENST00000867414, ENST00000867415, ENST00000867416, ENST00000867417, ENST00000867418, ENST00000946113, ENST00000946114, ENST00000946115

RefSeq mRNA: 4 — MANE Select: NM_015178 NM_001160036, NM_001160037, NM_001374791, NM_015178

CCDS: CCDS55210, CCDS55211, CCDS6034

Canonical transcript exons

ENST00000251822 — 10 exons

Exon	Start	End
ENSE00000684260	23007993	23008111
ENSE00000684262	23014690	23014778
ENSE00000684264	23015638	23015743
ENSE00000818481	23010538	23010688
ENSE00001306406	23017252	23020199
ENSE00001386526	23006728	23007746
ENSE00001855098	22999548	23000105
ENSE00003574510	23004425	23004626
ENSE00003611719	23005372	23005475
ENSE00003790514	23005960	23006145

Expression profiles

Bgee: expression breadth ubiquitous, 213 present calls, max score 93.88.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 12.9745 / max 147.8410, expressed in 1757 samples.

FANTOM5 promoters (21 alternative TSS)

Promoter ID	TPM avg	Samples expressed
87869	3.7923	1496
87871	2.7015	703
87876	2.0746	1254
87870	1.6328	786
87875	0.7329	433
87873	0.6741	285
87874	0.5042	222
205117	0.2219	33
87872	0.1310	56
87868	0.0774	35

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
upper lobe of left lung	UBERON:0008952	93.88	gold quality
upper lobe of lung	UBERON:0008948	93.21	gold quality
right frontal lobe	UBERON:0002810	93.07	gold quality
prefrontal cortex	UBERON:0000451	92.61	gold quality
caudate nucleus	UBERON:0001873	92.52	gold quality
putamen	UBERON:0001874	91.77	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	91.58	gold quality
right lung	UBERON:0002167	91.10	gold quality
Brodmann (1909) area 9	UBERON:0013540	90.95	gold quality
frontal cortex	UBERON:0001870	90.40	gold quality
cingulate cortex	UBERON:0003027	90.22	gold quality
neocortex	UBERON:0001950	90.21	gold quality
anterior cingulate cortex	UBERON:0009835	90.19	gold quality
cortical plate	UBERON:0005343	89.82	gold quality
nucleus accumbens	UBERON:0001882	89.14	gold quality
cerebral cortex	UBERON:0000956	88.79	gold quality
telencephalon	UBERON:0001893	88.75	gold quality
apex of heart	UBERON:0002098	88.49	gold quality
frontal pole	UBERON:0002795	88.25	gold quality
ventricular zone	UBERON:0003053	88.14	gold quality
primary visual cortex	UBERON:0002436	87.97	gold quality
superior frontal gyrus	UBERON:0002661	87.66	gold quality
stromal cell of endometrium	CL:0002255	87.42	gold quality
forebrain	UBERON:0001890	87.42	gold quality
right lobe of thyroid gland	UBERON:0001119	87.32	gold quality
postcentral gyrus	UBERON:0002581	87.12	gold quality
Brodmann (1909) area 10	UBERON:0013541	86.84	gold quality
Brodmann (1909) area 46	UBERON:0006483	86.65	gold quality
left lobe of thyroid gland	UBERON:0001120	86.54	gold quality
tibial artery	UBERON:0007610	86.50	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	21.82
E-MTAB-7303	no	926.56

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): E2F1

miRNA regulators (miRDB)

80 targeting RHOBTB2, 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-5193	100.00	67.26	1744
HSA-MIR-3925-3P	100.00	69.95	1237
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-3667-3P	99.99	67.17	1636
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-6845-3P	99.94	66.88	1439
HSA-MIR-515-5P	99.92	69.82	2343
HSA-MIR-519E-5P	99.92	69.62	2358
HSA-MIR-345-3P	99.89	70.23	1421
HSA-MIR-7162-3P	99.89	68.16	1682
HSA-MIR-129-5P	99.88	70.26	3273
HSA-MIR-7110-5P	99.80	67.84	1712
HSA-MIR-6842-5P	99.80	67.54	1587
HSA-MIR-6817-3P	99.79	68.35	2126
HSA-MIR-4319	99.76	69.83	2586
HSA-MIR-1976	99.74	65.48	1127
HSA-MIR-6752-3P	99.72	66.71	1587
HSA-MIR-670-5P	99.67	69.94	1565
HSA-MIR-6887-3P	99.66	67.83	1778
HSA-MIR-10394-5P	99.65	66.83	1852

Literature-anchored findings (GeneRIF, showing 26)

• A previously uncharacterized gene, DBC2 (deleted in breast cancer), was cloned from a homozygously deleted region at human chromosome 8p21. (PMID:12370419)
• two networks were found to react substantially to DBC2 expression–one of the networks regulates cell growth through cell-cycle control and apoptosis; the other network is related to cytoskeleton and membrane trafficking (PMID:15663929)
• DBC2 plays an essential role in microtubule-mediated VSVG transport from the endoplasmic reticulum to the Golgi apparatus. (PMID:17023000)
• Our results indicate that the down-regulation of CCND1 is an essential step for DBC2’s growth suppression of cancer cells. (PMID:17517369)
• These findings indicate that the resistant T-47D cells survive DBC2 induction by rapid destruction of DBC2 through 26S proteasome-mediated protein degradation. (PMID:17617377)
• The researchers isolated three novel mutations in the DBC2 gene in breast cancer families in Iran. (PMID:17653899)
• Mutations & allelic loss in the DBC2 gene are uncommon in gastric cancers in Korean patients, so it is unlikely to play a major role. 3 new polymorphisms in the coding region were found. (PMID:17906984)
• RhoBTB2 up-regulated during drug-induced apoptosis, with this being primarily dependent on E2F1. (PMID:18039672)
• aberrant methylation in DBC2 promoter may be responsible for the expression loss of DBC2 expression in bladder cancer and this hypermethylation event could play a crucial role in the early stage of bladder tumorigenesis. (PMID:18640857)
• CXCL14 is a gene target of RhoBTB2 and supports downregulation of CXCL14 as a functional outcome of RhoBTB2 loss in cancer. (PMID:18762809)
• The expression of Fas, CTLA-4 and RhoBTB2 at the mRNA level is involved in genesis and progression of breast cancer. (PMID:19173804)
• Frequent loss of RhoBTB2 expression is associated with sporadic breast cancer. (PMID:19937980)
• Ectopic expression of RhoBTB2 results in decreased phosphorylation of ezrin and Akt2 in both MDA-MB-231 and MDA-MB-435 cells. (PMID:20930524)
• RhoBTB2 is establishing itself as a tumor suppressor with increasing relevance towards malignancies. (PMID:20980811)
• Overexpression of RhoBTB2 in breast tumor cells significantly inhibited the proliferation and colony formation of tumor cells. In addition, RhoBTB2 also elevated the apoptotic ratio and caused typical changes of apoptotic morphology. (PMID:21801820)
• Loss of DBC2 expression is an early and progressive event in the development of lung adenocarcinoma. (PMID:22901165)
• Thus loss of DBC2 expression is caused by abnormal methylation of DBC2 and might have a role in breast cancer development. (PMID:23546941)
• ). The results demonstrated that aberrant methylation of RhoBTB2 may be responsible for the suppression of RhoBTB2 mRNA expression in breast cancer, a significant event during the genesis of breast cancer that correlated with progesterone receptor status (PMID:24356943)
• Mutation in the promoter and exon 7 of DBC2 gene is not common in the Chinese population and may not contribute to the susceptibility for breast cancer in China (PMID:24485767)
• data suggest a new paradigm for Hsp90-modulated assembly of a Cul3/DBC2 E3 ubiquitin ligase complex that may extend to other E3 ligase complexes. (PMID:24608665)
• these findings provide evidence that DBC2 suppresses tumorigenesis in breast cancer by ubiquitinating MSI2. (PMID:27941885)
• missense variants in the BTB-domain-encoding region of RHOBTB2 as causative for a developmental and epileptic encephalopathy. (PMID:29276004)
• RHOBTB2 Mutations Expand the Phenotypic Spectrum of Alternating Hemiplegia of Childhood. (PMID:33504645)
• Identification of RHOBTB2 aberration as an independent prognostic indicator in acute myeloid leukemia. (PMID:34074803)
• Mild head trauma: Acute encephalopathy trigger in children with RHOBTB2 de novo mutation. (PMID:36195378)
• Genotype-phenotype correlations in RHOBTB2-associated neurodevelopmental disorders. (PMID:37165955)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	rhobtb2a	ENSDARG00000074828
danio_rerio	rhobtb2b	ENSDARG00000089340
mus_musculus	Rhobtb2	ENSMUSG00000022075
rattus_norvegicus	Rhobtb2	ENSRNOG00000017373

Paralogs (22): RHOA (ENSG00000067560), CDC42 (ENSG00000070831), RHOBTB1 (ENSG00000072422), RHOV (ENSG00000104140), RND2 (ENSG00000108830), RND3 (ENSG00000115963), RHOU (ENSG00000116574), RHOQ (ENSG00000119729), RHOJ (ENSG00000126785), RHOT1 (ENSG00000126858), RAC2 (ENSG00000128340), RAC1 (ENSG00000136238), RHOF (ENSG00000139725), RHOT2 (ENSG00000140983), RHOB (ENSG00000143878), RHOC (ENSG00000155366), RHOBTB3 (ENSG00000164292), RHOH (ENSG00000168421), RAC3 (ENSG00000169750), RND1 (ENSG00000172602), RHOD (ENSG00000173156), RHOG (ENSG00000177105)

Protein

Protein identifiers

Rho-related BTB domain-containing protein 2 — Q9BYZ6 (reviewed: Q9BYZ6)

Alternative names: Deleted in breast cancer 2 gene protein, p83

All UniProt accessions (3): Q9BYZ6, A0A8I5KV41, E5RI44

UniProt curated annotations — full annotation on UniProt →

Function. Regulator of cell proliferation and apoptosis. It likely functions as a substrate-adapter that recruits key substrates, e.g. MSI2, to CUL3-based ubiquitin ligase complexes for degradation. Required for MSI2 ubiquitination and degradation.

Subunit / interactions. Interacts with HSP90AA1 and HSP90AB1. Forms a complex with CUL3 and RBX1. Interacts (via BTB 1 domain) with CUL3. Interacts with MSI2.

Tissue specificity. Ubiquitous, with highest levels in neural tissues. Expression is also detected in fetal lung, heart, and brain.

Post-translational modifications. Autoubiquitinated by RHOBTB2-CUL3-RBX1 ubiquitin ligase complex.

Disease relevance. Developmental and epileptic encephalopathy 64 (DEE64) [MIM:618004] A form of epileptic encephalopathy, a heterogeneous group of severe early-onset epilepsies characterized by refractory seizures, neurodevelopmental impairment, and poor prognosis. Development is normal prior to seizure onset, after which cognitive and motor delays become apparent. DEE64 is an autosomal dominant form characterized by onset of seizures usually in the first year of life. Seizure types are variable and include focal dyscognitive and generalized tonic-clonic seizures, as well as febrile seizures in the mildest affected individuals. Seizures tend to respond to medical treatment. The disease is caused by variants affecting the gene represented in this entry. Biallelic variants in RHOBTB2 may be involved in autosomal recessive neurodevelopmental disorders. Affected individuals present with variable neurodevelopmental phenotypes, including intellectual disability and seizures.

Similarity. Belongs to the small GTPase superfamily. Rho family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q9BYZ6-1	1	yes
Q9BYZ6-2	2
Q9BYZ6-3	3

RefSeq proteins (4): NP_001153508, NP_001153509, NP_001361720, NP_055993* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000210	BTB/POZ_dom	Domain
IPR001806	Small_GTPase	Family
IPR003578	Small_GTPase_Rho	Family
IPR011333	SKP1/BTB/POZ_sf	Homologous_superfamily
IPR027417	P-loop_NTPase	Homologous_superfamily

Pfam: PF00071, PF00651

UniProt features (38 total): sequence variant 19, mutagenesis site 4, binding site 3, region of interest 3, domain 2, splice variant 2, sequence conflict 2, compositionally biased region 2, chain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9BYZ6-F1	81.89	0.62

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Ligand- & substrate-binding residues (3): 140–143; 21–28; 84–88

Mutagenesis-validated functional residues (4):

Position	Phenotype
217	no effect on interaction with cul3. no effect on interaction with msi2.
219	no effect on interaction with cul3. no effect on interaction with msi2.
284	results in severely decreased interaction with cul3. no effect on interaction with msi2.
449	no effect on interaction with cul3. no effect on interaction with msi2.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-9013418	RHOBTB2 GTPase cycle

MSigDB gene sets: 435 (showing top): GOBP_REGULATION_OF_CELL_MORPHOGENESIS, GOBP_ESTABLISHMENT_OR_MAINTENANCE_OF_CELL_POLARITY, CGGAARNGGCNG_UNKNOWN, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GGGTGGRR_PAX4_03, CAGCTG_AP4_Q5, GOBP_REGULATION_OF_ACTIN_FILAMENT_BASED_PROCESS, CEBP_Q2, chr8p21, SHEDDEN_LUNG_CANCER_GOOD_SURVIVAL_A4, TGCTGAY_UNKNOWN, GOBP_ACTIN_FILAMENT_ORGANIZATION, SCHAEFFER_PROSTATE_DEVELOPMENT_48HR_DN, GOBP_POST_TRANSLATIONAL_PROTEIN_MODIFICATION

GO Biological Process (9): ubiquitin-dependent protein catabolic process (GO:0006511), actin filament organization (GO:0007015), establishment or maintenance of cell polarity (GO:0007163), signal transduction (GO:0007165), small GTPase-mediated signal transduction (GO:0007264), regulation of cell shape (GO:0008360), protein ubiquitination (GO:0016567), cortical cytoskeleton organization (GO:0030865), regulation of actin cytoskeleton organization (GO:0032956)

GO Molecular Function (6): GTPase activity (GO:0003924), GTP binding (GO:0005525), protein kinase binding (GO:0019901), ubiquitin-like ligase-substrate adaptor activity (GO:1990756), nucleotide binding (GO:0000166), protein binding (GO:0005515)

GO Cellular Component (6): cytoskeleton (GO:0005856), plasma membrane (GO:0005886), endosome membrane (GO:0010008), cytoplasmic vesicle (GO:0031410), Cul3-RING ubiquitin ligase complex (GO:0031463), cell projection (GO:0042995)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
RHOBTB GTPase Cycle	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
actin cytoskeleton organization	2
cellular process	2
protein ubiquitination	1
modification-dependent protein catabolic process	1
supramolecular fiber organization	1
cell communication	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
intracellular signaling cassette	1
regulation of cell morphogenesis	1
regulation of biological quality	1
protein modification by small protein conjugation	1
cytoskeleton organization	1
regulation of actin filament-based process	1
regulation of cytoskeleton organization	1
ribonucleoside triphosphate phosphatase activity	1
guanyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
kinase binding	1
enzyme-substrate adaptor activity	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
binding	1
intracellular membraneless organelle	1
membrane	1
cell periphery	1
endosome	1
cytoplasmic vesicle membrane	1
bounding membrane of organelle	1
cytoplasm	1
intracellular vesicle	1
cullin-RING ubiquitin ligase complex	1
cellular anatomical structure	1

Protein interactions and networks

STRING

2367 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RHOBTB2	CUL3	Q13618	858
RHOBTB2	SFTPC	P11686	650
RHOBTB2	PLIN3	O60664	583
RHOBTB2	TNFRSF10B	O14763	562
RHOBTB2	RHOBTB3	O94955	424
RHOBTB2	RHOT2	Q8IXI1	420
RHOBTB2	CENPV	Q7Z7K6	398
RHOBTB2	RHOT1	Q8IXI2	371
RHOBTB2	C8orf58	Q8NAV2	370
RHOBTB2	ATAD1	Q8NBU5	364
RHOBTB2	AKAP4	Q5JQC9	352
RHOBTB2	ZNF217	O75362	348
RHOBTB2	BTBD6	Q96KE9	345
RHOBTB2	BTBD1	Q9H0C5	341
RHOBTB2	ECT2	Q9H8V3	334

IntAct

21 interactions, top by confidence:

A	B	Type	Score
COPS6	RHOBTB1	psi-mi:“MI:0914”(association)	0.730
APBB3	RHOBTB1	psi-mi:“MI:0914”(association)	0.530
RHOBTB2	DUSP14	psi-mi:“MI:0914”(association)	0.530
CUL3	ZSWIM8	psi-mi:“MI:0914”(association)	0.530
GPS1	PXDNL	psi-mi:“MI:0914”(association)	0.530
BAG4	RHOBTB2	psi-mi:“MI:0915”(physical association)	0.370
RHOBTB2	CHEK2	psi-mi:“MI:0915”(physical association)	0.370
ERBB2	RHOBTB2	psi-mi:“MI:0915”(physical association)	0.370
RHOBTB2	FGFR2	psi-mi:“MI:0915”(physical association)	0.370
PALB2	RHOBTB2	psi-mi:“MI:0915”(physical association)	0.370
PPM1D	RHOBTB2	psi-mi:“MI:0915”(physical association)	0.370
RHOBTB2	PTPN1	psi-mi:“MI:0915”(physical association)	0.370
RHOBTB2	STK11	psi-mi:“MI:0915”(physical association)	0.370
CUL3	PXDNL	psi-mi:“MI:0914”(association)	0.350
PAK6	CNOT1	psi-mi:“MI:0914”(association)	0.350
COPS2	RHOBTB1	psi-mi:“MI:0914”(association)	0.350
COPS3	RHOBTB1	psi-mi:“MI:0914”(association)	0.350

BioGRID (189): Lrrc41 (Affinity Capture-Western), RHOBTB2 (Two-hybrid), RHOBTB2 (Two-hybrid), RHOBTB2 (Two-hybrid), RHOBTB2 (Two-hybrid), RHOBTB2 (Two-hybrid), RHOBTB2 (Two-hybrid), RHOBTB2 (Two-hybrid), RHOBTB2 (Two-hybrid), RHOBTB2 (Affinity Capture-Western), RHOBTB2 (Affinity Capture-Western), RHOBTB2 (Two-hybrid), RHOBTB2 (Two-hybrid), MSI2 (Biochemical Activity), MSI2 (Affinity Capture-Western)

ESM2 similar proteins: A2AGL3, A4FUD6, A4IHM6, B0LPN4, E9PZQ0, O35626, O94844, P16960, P51157, P51158, Q12829, Q15413, Q32LJ6, Q32NS2, Q3SWY9, Q3SX43, Q4R4K5, Q5E9J4, Q5F361, Q5FVD6, Q5FVJ7, Q5HYI8, Q5M8K8, Q5R8I6, Q5RCC1, Q5RFI2, Q5XGS8, Q5ZKR4, Q63486, Q66JN8, Q6GPS4, Q6NRC7, Q6TNS7, Q7L523, Q7SXV1, Q7ZUV0, Q80X95, Q8BHL5, Q8K0F1, Q91V93

Diamond homologs: A1L1L6, F4J0W4, O00212, O04369, O59781, O94844, P0CO78, P0CO79, P34144, P34150, P39722, P48554, P60763, P60764, Q17QI8, Q24814, Q298L5, Q2HJF8, Q2UM43, Q32LU1, Q35638, Q38912, Q38919, Q38937, Q39435, Q41253, Q41254, Q4I2W2, Q4PB75, Q4WN24, Q5B5L3, Q5E9M9, Q5ZM73, Q5ZM83, Q623S8, Q6C2J1, Q6CY37, Q6DIS1, Q6EP31, Q6FIR8

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 20 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Neddylation	6	16.7×	3e-05

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	4
Likely pathogenic	6
Uncertain significance	311
Likely benign	333
Benign	80

Top pathogenic / likely-pathogenic (10)

Variant ID	HGVS	Classification
1189651	NM_015178.3(RHOBTB2):c.1411G>A (p.Glu471Lys)	Pathogenic
2855187	NM_015178.3(RHOBTB2):c.293G>A (p.Gly98Glu)	Pathogenic
3390000	NM_015178.3(RHOBTB2):c.1113dup (p.Arg372fs)	Pathogenic
545418	NM_015178.3(RHOBTB2):c.1466G>A (p.Arg489Gln)	Pathogenic
2443571	NM_015178.3(RHOBTB2):c.280C>T (p.Arg94Cys)	Likely pathogenic
2500268	NM_015178.3(RHOBTB2):c.268C>T (p.His90Tyr)	Likely pathogenic
2584435	NM_015178.3(RHOBTB2):c.103G>T (p.Ala35Ser)	Likely pathogenic
4057336	NM_015178.3(RHOBTB2):c.656C>T (p.Ser219Phe)	Likely pathogenic
545421	NM_015178.3(RHOBTB2):c.1355C>G (p.Ala452Gly)	Likely pathogenic
800793	NM_015178.3(RHOBTB2):c.394C>T (p.Arg132Ter)	Likely pathogenic

SpliceAI

1457 predictions. Top by Δscore:

Variant	Effect	Δscore
8:23004421:TCAG:T	acceptor_loss	1.0000
8:23004422:CAG:C	acceptor_loss	1.0000
8:23004423:A:AG	acceptor_gain	1.0000
8:23004423:A:AT	acceptor_loss	1.0000
8:23004424:G:GC	acceptor_loss	1.0000
8:23004424:G:GG	acceptor_gain	1.0000
8:23004623:GGAG:G	donor_gain	1.0000
8:23004624:G:GT	donor_gain	1.0000
8:23004625:AGGT:A	donor_loss	1.0000
8:23004626:GGTA:G	donor_loss	1.0000
8:23004627:G:GA	donor_loss	1.0000
8:23004628:T:A	donor_loss	1.0000
8:23005367:CCCAG:C	acceptor_loss	1.0000
8:23005368:CCAGG:C	acceptor_loss	1.0000
8:23005369:CAGG:C	acceptor_loss	1.0000
8:23005370:A:AT	acceptor_loss	1.0000
8:23005371:G:GT	acceptor_loss	1.0000
8:23005473:G:GT	donor_gain	1.0000
8:23005473:G:T	donor_gain	1.0000
8:23006125:GGC:G	donor_gain	1.0000
8:23007742:CTCAG:C	donor_loss	1.0000
8:23007743:TCAG:T	donor_loss	1.0000
8:23007744:CAG:C	donor_loss	1.0000
8:23007745:AGG:A	donor_loss	1.0000
8:23007748:T:A	donor_loss	1.0000
8:23008110:AGG:A	donor_loss	1.0000
8:23008112:GTA:G	donor_loss	1.0000
8:23008113:T:G	donor_loss	1.0000
8:23010536:A:AG	acceptor_gain	1.0000
8:23010536:AG:A	acceptor_gain	1.0000

AlphaMissense

4796 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
8:23004478:T:A	I15N	1.000
8:23004480:A:G	K16E	1.000
8:23004482:G:C	K16N	1.000
8:23004482:G:T	K16N	1.000
8:23004483:T:C	C17R	1.000
8:23004484:G:A	C17Y	1.000
8:23004485:C:G	C17W	1.000
8:23004487:T:A	V18D	1.000
8:23004495:G:A	G21R	1.000
8:23004495:G:C	G21R	1.000
8:23004495:G:T	G21W	1.000
8:23004496:G:A	G21E	1.000
8:23004496:G:T	G21V	1.000
8:23004498:G:C	D22H	1.000
8:23004498:G:T	D22Y	1.000
8:23004499:A:C	D22A	1.000
8:23004499:A:G	D22G	1.000
8:23004499:A:T	D22V	1.000
8:23004503:C:A	N23K	1.000
8:23004503:C:G	N23K	1.000
8:23004510:G:C	G26R	1.000
8:23004511:G:A	G26D	1.000
8:23004511:G:T	G26V	1.000
8:23004513:A:C	K27Q	1.000
8:23004514:A:T	K27M	1.000
8:23004515:G:C	K27N	1.000
8:23004515:G:T	K27N	1.000
8:23004517:C:T	T28I	1.000
8:23004523:T:C	L30P	1.000
8:23004526:T:A	I31N	1.000

dbSNP variants (sampled 300 via entrez): RS1000041077 (8:23015119 CTCCCTTAA>C), RS1000147981 (8:22969937 A>T), RS1000178284 (8:23008996 G>A), RS1000209745 (8:23009365 G>C), RS1000212711 (8:22968663 C>T), RS1000241315 (8:22987250 C>T), RS1000359343 (8:23003130 C>T), RS1000368675 (8:22962744 CCTGA>C), RS1000404322 (8:22997402 A>C), RS1000461646 (8:22974918 CG>C), RS1000534228 (8:23004142 G>A,C), RS1000544354 (8:23009400 G>A), RS1000631471 (8:22988246 G>A), RS1000690902 (8:22993911 G>A), RS1000696827 (8:22986908 C>A)

Disease associations

OMIM: gene MIM:607352 | disease phenotypes: MIM:618004, MIM:312750

GenCC curated gene-disease

Disease	Classification	Inheritance
developmental and epileptic encephalopathy, 64	Strong	Autosomal dominant
complex neurodevelopmental disorder	Strong	Autosomal recessive

ClinGen Gene-Disease Validity (2)

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

Disease	Classification	Inheritance
complex neurodevelopmental disorder	Definitive	AD
complex neurodevelopmental disorder	Definitive	AR

Mondo (6): developmental and epileptic encephalopathy, 64 (MONDO:0033373), prostate cancer (MONDO:0008315), Rett syndrome (MONDO:0010726), choreatic disease (MONDO:0001595), dystonic disorder (MONDO:0003441), complex neurodevelopmental disorder (MONDO:0100038)

Orphanet (4): Familial prostate cancer (Orphanet:1331), Atypical Rett syndrome (Orphanet:3095), Rett syndrome (Orphanet:778), Benign hereditary chorea (Orphanet:1429)

HPO phenotypes

149 total (30 of 149 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000054	Micropenis
HP:0000070	Ureterocele
HP:0000110	Renal dysplasia
HP:0000175	Cleft palate
HP:0000179	Thick lower lip vermilion
HP:0000219	Thin upper lip vermilion
HP:0000252	Microcephaly
HP:0000268	Dolichocephaly
HP:0000286	Epicanthus
HP:0000294	Low anterior hairline
HP:0000297	Facial hypotonia
HP:0000319	Smooth philtrum
HP:0000340	Sloping forehead
HP:0000343	Long philtrum
HP:0000347	Micrognathia
HP:0000348	High forehead
HP:0000400	Macrotia
HP:0000455	Broad nasal tip
HP:0000463	Anteverted nares
HP:0000486	Strabismus
HP:0000490	Deeply set eye
HP:0000527	Long eyelashes
HP:0000565	Esotropia
HP:0000574	Thick eyebrow
HP:0000577	Exotropia
HP:0000639	Nystagmus
HP:0000657	Oculomotor apraxia
HP:0000687	Widely spaced teeth
HP:0000708	Atypical behavior

GWAS associations

8 associations (top):

Study	Trait	p-value
GCST004484_6	Plasma trimethylamine N-oxide levels	3.000000e-07
GCST004710_4	Renal cell carcinoma	6.000000e-09
GCST005901_1	Survival in breast cancer (estrogen-receptor positive)	2.000000e-08
GCST005901_2	Survival in breast cancer (estrogen-receptor positive)	2.000000e-07
GCST006136_8	Alzheimer’s disease progression score	7.000000e-07
GCST008163_475	Height	1.000000e-06
GCST90011899_134	Aspartate aminotransferase levels	3.000000e-12
GCST90013410_39	Basal cell carcinoma	2.000000e-08

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0005691	plasma trimethylamine N-oxide measurement
EFO:0000482	event free survival time
EFO:0006514	Alzheimer’s disease biomarker measurement
EFO:0004736	aspartate aminotransferase measurement

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D002819	Chorea	C10.228.662.262.249; C10.597.350.250; C23.888.592.350.250
D020821	Dystonic Disorders	C10.228.662.300
D011471	Prostatic Neoplasms	C04.588.945.440.770; C12.100.500.260.750; C12.100.500.565.625; C12.200.294.260.750; C12.200.294.565.625; C12.200.758.409.750; C12.900.619.750
D015518	Rett Syndrome	C10.597.606.360.455.937; C16.320.322.500.937; C16.320.400.525.937

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

38 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases expression, affects expression, affects cotreatment	6
bisphenol A	affects cotreatment, increases methylation, increases expression	3
sodium arsenite	decreases expression, increases expression	2
Acetaminophen	increases expression	2
Tretinoin	decreases expression, increases expression	2
GSK-J4	decreases expression	1
dicrotophos	increases expression	1
alpha phellandrene	increases expression	1
triphenyl phosphate	affects expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
perfluorooctanoic acid	increases expression, affects cotreatment	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression	1
di-n-butylphosphoric acid	affects expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
dorsomorphin	increases expression, affects cotreatment	1
Bortezomib	increases response to substance	1
Resveratrol	affects cotreatment, decreases expression	1
Sunitinib	increases expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Air Pollutants	decreases expression, increases abundance	1
Benzo(a)pyrene	affects methylation	1
Cisplatin	increases expression	1
Cosmetics	affects cotreatment, increases expression	1
Doxorubicin	decreases expression	1
Flame Retardants	affects cotreatment, increases expression	1
Lipopolysaccharides	decreases expression, affects response to substance, increases expression	1
Mercury	increases expression	1
Plant Extracts	affects cotreatment, decreases expression	1
Plasticizers	affects cotreatment, increases expression	1
Silicon Dioxide	decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00029224	PHASE4	COMPLETED	Treatment With Zoledronic Acid in Patients With Breast Cancer, Multiple Myeloma, and Prostate Cancer With Cancer Related Bone Lesions
NCT00035997	PHASE4	COMPLETED	Open-label Trial on the Effect of I.V. Zoledronic Acid 4 mg on Bone Density in Hormone Sensitive Prostate Cancer Patients With Bone Metastasis
NCT00063609	PHASE4	COMPLETED	The Effect of Zoledronic Acid on Bone Loss in Prostate Cancer Patients Undergoing Androgen Deprivation Therapy
NCT00103623	PHASE4	SUSPENDED	The Plenaxis® Experience Study
NCT00106392	PHASE4	COMPLETED	A Safety and Efficacy Study of Prograf in the Prevention of Erectile Dysfunction After Radical Prostatectomy
NCT00185029	PHASE4	UNKNOWN	MR-Lymphography and Lymph Node Staging in Prostate Cancer
NCT00199485	PHASE4	COMPLETED	Angelica Sinensis for the Treatment of Hot Flashes in Men Undergoing LHRH Therapy for Prostate Cancer
NCT00219219	PHASE4	COMPLETED	Zoledronic Acid in the Prevention of Skeletal-related Events in Hormone Refractory and Hormone-sensitive Prostate Cancer Patients With Bone Metastases
NCT00219271	PHASE4	COMPLETED	Effect Of Zoledronic Acid On Circulating And Bone Marrow-Residing Prostate Cancer Cells In Patients With Clinically Localized Prostate Cancer
NCT00237146	PHASE4	COMPLETED	Study to Evaluate Zoledronic Acid on Quality of Life and Skeletal-related Events as Adjuvant Treatment in Patients With Hormone-naïve Prostate Cancer and Bone Metastasis Who Have Undergone Orchiectomy
NCT00242554	PHASE4	COMPLETED	Open-label Phase IV Clinical Trial to Evaluate the Safety and Tolerability of Zoledronic Acid in Patients With Prostate Cancer and Bone Metastases
NCT00280098	PHASE4	COMPLETED	Docetaxel in the Treatment of Hormone Refractory Prostate Cancer
NCT00293696	PHASE4	COMPLETED	Casodex/Zoladex Biomarkers in Localised Prostate Cancer
NCT00334139	PHASE4	COMPLETED	Effect of Zoledronic Acid on Bone Metabolism in Patients With Bone Metastasis and Prostate or Breast Cancer
NCT00375765	PHASE4	COMPLETED	Effects On Dihydrotestosterone Regulated Gene Expression In Benign Prostatic Hyperplasia Or Prostate Cancer
NCT00391690	PHASE4	COMPLETED	Evaluation of Bone Markers as Diagnostic Tools for Early Detection of Bone Metastases in Patients With High Risk Prostate Cancer
NCT00422708	PHASE4	COMPLETED	Local Anesthesia for Prostate Biopsy
NCT00526331	PHASE4	COMPLETED	Evaluation of Arterial Pressure Based Cardiac Output for Goal-Directed Perioperative Therapy
NCT00590213	PHASE4	COMPLETED	Compare the Value of Prophylactic Versus Therapeutic Breast Radiotherapy in CASODEX
NCT00629330	PHASE4	TERMINATED	Dissemination of Prostate Cancer Screening to PCP’s in African American Communities
NCT00771966	PHASE4	COMPLETED	Radical Prostatectomy and Perioperative Fluid Therapy
NCT00805701	PHASE4	COMPLETED	Study Assessing The Efficacy And Safety Of Avodart (Dutasteride) At Improving Urinary Symptoms In Men With Prostate Cancer Who Are Undergoing Seed Implantation
NCT00859027	PHASE4	COMPLETED	Effect Of Risedronate On Bone Mass In Older Men Receiving Neoadjuvant Therapy For Prostate Cancer
NCT00906269	PHASE4	UNKNOWN	Can Hyperbaric Oxygen Improve Erectile Function Following Surgery for Prostate Cancer
NCT00953277	PHASE4	COMPLETED	Study of Nerve Reconstruction Using AVANCE in Subjects Who Undergo Robotic Assisted Prostatectomy for Treatment of Prostate Cancer
NCT00982800	PHASE4	COMPLETED	Does Postoperative Gabapentin Reduce Pain, Opioid Consumption and Anxiety and Have a Positive Effect on Health Related Quality of Life After Radical Prostatectomy?
NCT01083199	PHASE4	COMPLETED	Global Performance Evaluation of the AMS CONTINUUM™ Device
NCT01136226	PHASE4	COMPLETED	Evaluate Recovery of Testosterone for Patients Using Eligard
NCT01161563	PHASE4	COMPLETED	Randomized Crossover Trial to Assess the Tolerability of Gonadotropin Releasing Hormone (GnRH) Analogue Administration
NCT01230905	PHASE4	COMPLETED	Study to Monitor the Effects of Androgen Suppression Treatment on the Heart
NCT01296672	PHASE4	COMPLETED	3 Month Finasteride Challenge Test Can Significantly Improve the Performance of Screening for Prostate Cancer
NCT01365143	PHASE4	TERMINATED	Prospective Randomized Trial Comparing Robotic Versus Open Radical Prostatectomy
NCT01379742	PHASE4	UNKNOWN	Comparison of Between ThinSeed™ and OncoSeed™ for Permanent Prostate Brachytherapy
NCT01486563	PHASE4	COMPLETED	Hydroxyethyl Starch and Renal Function After Radical Prostatectomy
NCT01511874	PHASE4	COMPLETED	Efficacy and Safety Study of ELIGARD 22.5mg With Prostate Cancer
NCT01512472	PHASE4	TERMINATED	Firmagon (Degarelix) Intermittent Therapy
NCT01547416	PHASE4	COMPLETED	The Effect of Combined General/Epidural Anesthesia Versus General Anesthesia on Diaphragmatic Function
NCT01571544	PHASE4	COMPLETED	The Use of Thermal Suits as Preventing Hypothermia During Surgery
NCT01581749	PHASE4	UNKNOWN	Evaluation of Truebeam for Low-Intermediate Risk Prostate Cancer
NCT01649635	PHASE4	COMPLETED	Study of Cabazitaxel Combined With Prednisone and Prophylaxis of Neutropenia Complications in the Treatment of Patients With Metastatic Castration-resistant Prostate Cancer