CCNB1IP1

Summary

CCNB1IP1 (cyclin B1 interacting protein 1, HGNC:19437) is a protein-coding gene on chromosome 14q11.2, encoding E3 ubiquitin-protein ligase CCNB1IP1 (Q9NPC3). Ubiquitin E3 ligase that acts as a limiting factor for crossing-over during meiosis: required during zygonema to limit the colocalization of RNF212 with MutS-gamma-associated recombination sites and thereby establish early differentiation of crossover and non-crossover sites.

HEI10 is a member of the E3 ubiquitin ligase family and functions in progression of the cell cycle through G(2)/M.

Source: NCBI Gene 57820 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 13 total — 1 pathogenic
• MANE Select transcript: NM_021178

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:19437
Approved symbol	CCNB1IP1
Name	cyclin B1 interacting protein 1
Location	14q11.2
Locus type	gene with protein product
Status	Approved
Aliases	HEI10
Ensembl gene	ENSG00000100814
Ensembl biotype	protein_coding
OMIM	608249
Entrez	57820

Gene structure

Transcript identifiers

Ensembl transcripts: 44 — 37 protein_coding, 4 protein_coding_CDS_not_defined, 3 nonsense_mediated_decay

ENST00000353689, ENST00000358932, ENST00000398160, ENST00000398163, ENST00000398169, ENST00000553291, ENST00000553516, ENST00000554047, ENST00000554184, ENST00000555348, ENST00000555963, ENST00000556563, ENST00000556854, ENST00000557114, ENST00000557665, ENST00000893208, ENST00000893209, ENST00000893210, ENST00000893211, ENST00000893212, ENST00000893213, ENST00000893214, ENST00000931440, ENST00000931441, ENST00000931442, ENST00000931443, ENST00000931444, ENST00000931445, ENST00000931446, ENST00000931447, ENST00000931448, ENST00000931449, ENST00000931450, ENST00000931451, ENST00000931452, ENST00000931453, ENST00000931454, ENST00000931455, ENST00000931456, ENST00000931457, ENST00000931458, ENST00000931459, ENST00000947396, ENST00000947397

RefSeq mRNA: 3 — MANE Select: NM_021178 NM_021178, NM_182849, NM_182852

CCDS: CCDS9547

Canonical transcript exons

ENST00000358932 — 7 exons

Exon	Start	End
ENSE00000888897	20316227	20316560
ENSE00001096336	20326716	20326793
ENSE00001398113	20329174	20329373
ENSE00001531896	20311370	20311752
ENSE00001532016	20325539	20325653
ENSE00002459134	20333254	20333279
ENSE00003549238	20313468	20313801

Expression profiles

Bgee: expression breadth ubiquitous, 284 present calls, max score 97.86.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 18.3625 / max 448.9475, expressed in 1752 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
142013	17.6109	1743
142014	0.7516	497

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
left ovary	UBERON:0002119	97.86	gold quality
ganglionic eminence	UBERON:0004023	97.49	gold quality
right ovary	UBERON:0002118	97.39	gold quality
embryo	UBERON:0000922	97.23	gold quality
ovary	UBERON:0000992	97.20	gold quality
mucosa of stomach	UBERON:0001199	97.06	gold quality
cartilage tissue	UBERON:0002418	96.71	gold quality
ventricular zone	UBERON:0003053	96.63	gold quality
body of uterus	UBERON:0009853	96.40	gold quality
apex of heart	UBERON:0002098	96.07	gold quality
right atrium auricular region	UBERON:0006631	96.02	gold quality
heart left ventricle	UBERON:0002084	95.98	gold quality
renal medulla	UBERON:0000362	95.95	gold quality
cardiac ventricle	UBERON:0002082	95.94	gold quality
endocervix	UBERON:0000458	95.84	gold quality
right lung	UBERON:0002167	95.83	gold quality
body of pancreas	UBERON:0001150	95.74	gold quality
heart	UBERON:0000948	95.66	gold quality
popliteal artery	UBERON:0002250	95.65	gold quality
tibial artery	UBERON:0007610	95.64	gold quality
cardiac atrium	UBERON:0002081	95.60	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	95.37	gold quality
aorta	UBERON:0000947	95.25	gold quality
gastrocnemius	UBERON:0001388	95.11	gold quality
muscle of leg	UBERON:0001383	95.01	gold quality
lower esophagus muscularis layer	UBERON:0035833	94.98	gold quality
lower esophagus	UBERON:0013473	94.94	gold quality
left uterine tube	UBERON:0001303	94.83	gold quality
thoracic aorta	UBERON:0001515	94.78	gold quality
ascending aorta	UBERON:0001496	94.77	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	7.09
E-CURD-112	yes	5.77

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

4 targeting CCNB1IP1, 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-4437	99.52	65.29	1266
HSA-MIR-504-3P	99.30	67.18	1745
HSA-MIR-939-3P	98.97	65.07	2347
HSA-MIR-367-5P	98.84	67.18	902

Literature-anchored findings (GeneRIF, showing 3)

• HEI10 defines a divergent class of E3 ubiquitin ligase, functioning in progression through G(2)/M. (PMID:12612082)
• The cyclin B-binding protein and cell cycle regulator HEI10 is identified as a novel merlin-binding partner; interaction with merlin affects HEI10 protein levels. (PMID:16532029)
• CCNB1IP1 prevents ubiquitination-mediated destabilization of MYCN and potentiates tumourigenesis of MYCN-amplificated neuroblastoma. (PMID:37461251)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	CCNB1IP1	ENSDARG00000104639
mus_musculus	Ccnb1ip1	ENSMUSG00000071470
rattus_norvegicus	Ccnb1ip1	ENSRNOG00000026056

Protein

Protein identifiers

E3 ubiquitin-protein ligase CCNB1IP1 — Q9NPC3 (reviewed: Q9NPC3)

Alternative names: Cyclin-B1-interacting protein 1, Human enhancer of invasion 10, RING-type E3 ubiquitin transferase CCNB1IP1

All UniProt accessions (7): Q9NPC3, A0A384MR52, G3V5E6, G3V5Q4, G3V5S3, H0YJ70, H0YJB2

UniProt curated annotations — full annotation on UniProt →

Function. Ubiquitin E3 ligase that acts as a limiting factor for crossing-over during meiosis: required during zygonema to limit the colocalization of RNF212 with MutS-gamma-associated recombination sites and thereby establish early differentiation of crossover and non-crossover sites. Later, it is directed by MutL-gamma to stably accumulate at designated crossover sites. Probably promotes the dissociation of RNF212 and MutS-gamma to allow the progression of recombination and the implementation of the final steps of crossing over. Modulates cyclin-B levels and participates in the regulation of cell cycle progression through the G2 phase. Overexpression causes delayed entry into mitosis.

Subunit / interactions. Interacts with CCNB1, UBE2L3 and NF2.

Subcellular location. Nucleus. Chromosome.

Tissue specificity. Highly expressed in heart. Detected at intermediate levels in liver and kidney, and at low levels in placenta, brain and lung.

Post-translational modifications. Ubiquitinated; autoubiquitinated. Phosphorylated by CDK1 on serine or threonine residues (in vitro).

Pathway. Protein modification; protein ubiquitination.

RefSeq proteins (3): NP_067001, NP_878269, NP_878272 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001841	Znf_RING	Domain
IPR042448	CCNB1IP1	Family

Pfam: PF14634

UniProt features (6 total): mutagenesis site 3, chain 1, zinc finger region 1, coiled-coil region 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
9GES	X-RAY DIFFRACTION	2.43

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NPC3-F1	77.60	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.

Mutagenesis-validated functional residues (3):

Position	Phenotype
28	abrogates induction of filamentous growth in yeast; when associated with a-30 and a-33.
30	abrogates induction of filamentous growth in yeast; when associated with a-28 and a-33.
33	abrogates induction of filamentous growth in yeast; when associated with a-28 and a-30.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 190 (showing top): GOBP_MEIOTIC_CHROMOSOME_SEGREGATION, GOBP_CHROMOSOME_ORGANIZATION, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, BHATI_G2M_ARREST_BY_2METHOXYESTRADIOL_DN, TGACCTY_ERR1_Q2, GOBP_MALE_GAMETE_GENERATION, GOBP_BLASTOCYST_FORMATION, YY1_Q6, RODWELL_AGING_KIDNEY_NO_BLOOD_DN, MONNIER_POSTRADIATION_TUMOR_ESCAPE_UP, CHEN_LVAD_SUPPORT_OF_FAILING_HEART_UP, CCANNAGRKGGC_UNKNOWN, CREIGHTON_ENDOCRINE_THERAPY_RESISTANCE_1, GOBP_IN_UTERO_EMBRYONIC_DEVELOPMENT, GOBP_ORGANELLE_FISSION

GO Biological Process (6): blastocyst formation (GO:0001825), reciprocal meiotic recombination (GO:0007131), spermatid development (GO:0007286), protein ubiquitination (GO:0016567), chiasma assembly (GO:0051026), meiotic cell cycle (GO:0051321)

GO Molecular Function (6): zinc ion binding (GO:0008270), identical protein binding (GO:0042802), ubiquitin protein ligase activity (GO:0061630), protein binding (GO:0005515), transferase activity (GO:0016740), metal ion binding (GO:0046872)

GO Cellular Component (4): synaptonemal complex (GO:0000795), condensed nuclear chromosome (GO:0000794), nucleus (GO:0005634), chromosome (GO:0005694)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
meiotic cell cycle process	2
blastocyst development	1
anatomical structure formation involved in morphogenesis	1
meiosis I	1
reciprocal homologous recombination	1
germ cell development	1
spermatid differentiation	1
protein modification by small protein conjugation	1
homologous chromosome pairing at meiosis	1
reciprocal meiotic recombination	1
cellular component assembly	1
cell cycle	1
sexual reproduction	1
reproductive process	1
meiotic nuclear division	1
transition metal ion binding	1
protein binding	1
ubiquitin-protein transferase activity	1
ubiquitin-like protein ligase activity	1
binding	1
catalytic activity	1
cation binding	1
synaptonemal structure	1
nuclear chromosome	1
condensed chromosome	1
nucleus	1
intracellular membrane-bounded organelle	1
intracellular membraneless organelle	1

Protein interactions and networks

STRING

646 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CCNB1IP1	RNF212	Q495C1	905
CCNB1IP1	COX6C	P09669	800
CCNB1IP1	F5H6H0	F5H6H0	766
CCNB1IP1	MSH4	O15457	746
CCNB1IP1	DPT	Q07507	715
CCNB1IP1	RAD51B	O15315	709
CCNB1IP1	CCNB1	P14635	705
CCNB1IP1	HFM1	A2PYH4	691
CCNB1IP1	ALDH2	P05091	654
CCNB1IP1	LPP	Q93052	648
CCNB1IP1	LHFPL6	Q9Y693	636
CCNB1IP1	CNTD1	Q8N815	606
CCNB1IP1	MSH5	O43196	603
CCNB1IP1	FH	P07954	546
CCNB1IP1	XRCC5	P13010	526

IntAct

53 interactions, top by confidence:

A	B	Type	Score
CCNB1	CDK1	psi-mi:“MI:0217”(phosphorylation reaction)	0.980
CCNB1IP1	PRKAA2	psi-mi:“MI:0915”(physical association)	0.670
EPM2AIP1	CCNB1IP1	psi-mi:“MI:0915”(physical association)	0.670
KRT15	CCNB1IP1	psi-mi:“MI:0915”(physical association)	0.670
CCNB1IP1	KEAP1	psi-mi:“MI:0915”(physical association)	0.670
CCNB1IP1	EPM2AIP1	psi-mi:“MI:0915”(physical association)	0.670
CCNB1IP1	KRT15	psi-mi:“MI:0915”(physical association)	0.670
CCNB1IP1	CCNB1IP1	psi-mi:“MI:0915”(physical association)	0.670
PRKAA2	CCNB1IP1	psi-mi:“MI:0915”(physical association)	0.670
KEAP1	CCNB1IP1	psi-mi:“MI:0915”(physical association)	0.670
CCNB1IP1	H1-3	psi-mi:“MI:0915”(physical association)	0.590
PRD1	CCNB1IP1	psi-mi:“MI:0915”(physical association)	0.560
CCNB1IP1	PRD1	psi-mi:“MI:0915”(physical association)	0.560
CUL5	CCNB1IP1	psi-mi:“MI:0915”(physical association)	0.560
SYT17	CCNB1IP1	psi-mi:“MI:0915”(physical association)	0.560
NTAQ1	CCNB1IP1	psi-mi:“MI:0915”(physical association)	0.560
HTT	CCNB1IP1	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (39): CCNB1IP1 (Two-hybrid), CCNB1IP1 (Two-hybrid), CCNB1IP1 (Two-hybrid), CCNB1IP1 (Two-hybrid), CCNB1IP1 (Two-hybrid), UBE2L3 (Reconstituted Complex), CCNB1IP1 (Biochemical Activity), HIST1H1D (Affinity Capture-MS), CCNB1IP1 (Two-hybrid), EPM2AIP1 (Two-hybrid), CCNB1IP1 (Affinity Capture-MS), HIST1H1D (Affinity Capture-MS), CCNB1IP1 (Two-hybrid), SYT17 (Two-hybrid), WDYHV1 (Two-hybrid)

ESM2 similar proteins: A0A1P8ASY1, A0JMA8, A1A5P5, A2XW69, A2ZAC2, A5HEI1, C6KRL6, D3Z3K2, E7F187, O15111, O23463, O76908, O94271, P30630, P38533, Q05B30, Q10198, Q336R3, Q3SWY8, Q4R4A2, Q5M8Y7, Q5U245, Q5U4X5, Q5XG48, Q66IH2, Q6DRJ7, Q6NRV0, Q76I89, Q7XHR2, Q7XU27, Q7Z3E5, Q80WE4, Q84RR2, Q8AWF5, Q8CHS8, Q8H1E8, Q8IMM9, Q8MYP1, Q94166, Q949V6

Diamond homologs: D3Z3K2, Q9NPC3, F4HRI2, I6PL68

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
Ub:E2	“up-regulates activity”	CCNB1IP1	ubiquitination

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	3
Likely benign	0
Benign	2

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
1808729	GRCh37/hg19 14q11.2(chr14:20690196-23114522)x1	Pathogenic

SpliceAI

1670 predictions. Top by Δscore:

Variant	Effect	Δscore
14:20313463:CTTA:C	donor_loss	1.0000
14:20313464:TTACC:T	donor_loss	1.0000
14:20313465:TACCT:T	donor_loss	1.0000
14:20313466:A:AC	donor_gain	1.0000
14:20313466:ACC:A	donor_loss	1.0000
14:20313467:C:CC	donor_gain	1.0000
14:20313467:C:CT	donor_loss	1.0000
14:20313797:TGTAC:T	acceptor_gain	1.0000
14:20313798:GTAC:G	acceptor_gain	1.0000
14:20313799:TAC:T	acceptor_gain	1.0000
14:20313800:AC:A	acceptor_gain	1.0000
14:20313801:CC:C	acceptor_gain	1.0000
14:20313802:C:CC	acceptor_gain	1.0000
14:20313805:G:GC	acceptor_gain	1.0000
14:20313809:C:CT	acceptor_gain	1.0000
14:20313809:C:T	acceptor_gain	1.0000
14:20313810:A:T	acceptor_gain	1.0000
14:20314506:C:CA	donor_gain	1.0000
14:20316223:TAA:T	donor_loss	1.0000
14:20316224:AAC:A	donor_loss	1.0000
14:20316226:C:A	donor_loss	1.0000
14:20316556:GAGGC:G	acceptor_gain	1.0000
14:20316558:GGC:G	acceptor_gain	1.0000
14:20316559:GC:G	acceptor_gain	1.0000
14:20316560:CC:C	acceptor_gain	1.0000
14:20316561:C:CC	acceptor_gain	1.0000
14:20316561:CTAA:C	acceptor_loss	1.0000
14:20316562:T:G	acceptor_loss	1.0000
14:20325562:A:AC	donor_gain	1.0000
14:20325562:AT:A	donor_gain	1.0000

AlphaMissense

1841 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
14:20313578:A:G	L174P	1.000
14:20313599:C:G	R167P	1.000
14:20313608:A:G	L164P	1.000
14:20316238:A:G	W96R	1.000
14:20316238:A:T	W96R	1.000
14:20316239:G:C	F95L	1.000
14:20316239:G:T	F95L	1.000
14:20316240:A:G	F95S	1.000
14:20316241:A:G	F95L	1.000
14:20316250:C:G	A92P	1.000
14:20316285:A:G	L80P	1.000
14:20316288:C:T	G79E	1.000
14:20316289:C:G	G79R	1.000
14:20316289:C:T	G79R	1.000
14:20316371:G:C	C51W	1.000
14:20316372:C:A	C51F	1.000
14:20316372:C:G	C51S	1.000
14:20316372:C:T	C51Y	1.000
14:20316373:A:G	C51R	1.000
14:20316373:A:T	C51S	1.000
14:20316380:A:C	C48W	1.000
14:20316381:C:G	C48S	1.000
14:20316381:C:T	C48Y	1.000
14:20316382:A:G	C48R	1.000
14:20316382:A:T	C48S	1.000
14:20316414:C:T	G37D	1.000
14:20316425:A:C	C33W	1.000
14:20316426:C:T	C33Y	1.000
14:20316427:A:G	C33R	1.000
14:20316429:A:G	F32S	1.000

dbSNP variants (sampled 300 via entrez): RS1000017982 (14:20313782 T>C), RS1000090583 (14:20315873 G>A,C,T), RS1000395161 (14:20334882 G>A,C), RS1000662257 (14:20314041 C>T), RS1000725310 (14:20331538 T>A), RS1000904411 (14:20325052 A>G), RS1001139996 (14:20317033 C>T), RS1001144314 (14:20330415 A>G), RS1001171181 (14:20332904 G>A), RS1001188273 (14:20329985 T>G), RS1001250740 (14:20323115 C>T), RS1001266146 (14:20332520 A>G), RS1001456954 (14:20325774 G>A), RS1001867259 (14:20325346 G>A,C), RS1001944977 (14:20312512 T>C)

Disease associations

OMIM: gene MIM:608249 | disease phenotypes:

GenCC curated gene-disease

Mondo (1): 14q11.2 microduplication syndrome (MONDO:0016835)

Orphanet (1): 14q11.2 microduplication syndrome (Orphanet:261229)

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases expression, decreases methylation, increases expression	4
sodium arsenite	decreases expression	3
Air Pollutants	increases oxidation, increases expression, affects cotreatment, increases abundance	2
Benzo(a)pyrene	decreases expression	2
Tunicamycin	increases expression	2
Cadmium Chloride	decreases expression, increases expression	2
dicrotophos	decreases expression	1
alpha-pinene	increases oxidation, increases abundance, affects cotreatment	1
propionaldehyde	increases methylation	1
bisphenol A	decreases expression	1
nonanal	increases methylation	1
n-hexanal	increases methylation	1
beta-lapachone	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
cobaltous chloride	increases expression	1
butyraldehyde	increases methylation	1
zinc chromate	increases abundance, increases expression	1
potassium chromate(VI)	affects cotreatment, increases expression	1
caprylic aldehyde	increases methylation	1
methacrylaldehyde	affects cotreatment, increases oxidation, increases abundance	1
epigallocatechin gallate	affects cotreatment, increases expression	1
pentanal	increases methylation	1
heptanal	increases methylation	1
bicalutamide	increases expression	1
chromium hexavalent ion	increases abundance, increases expression	1
perfluorooctane sulfonic acid	increases expression	1
pentabromodiphenyl ether	increases expression	1
14-deoxy-11,12-didehydroandrographolide	increases expression	1
abrine	increases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	increases expression	1

Cellosaurus cell lines

3 cell lines: 3 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_1536	NCI-H2171	Cancer cell line	Male
CVCL_SH32	HAP1 CCNB1IP1 (-) 1	Cancer cell line	Male
CVCL_XM53	HAP1 CCNB1IP1 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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