CGB5

Summary

CGB5 (chorionic gonadotropin subunit beta 5, HGNC:16452) is a protein-coding gene on chromosome 19q13.33, encoding Choriogonadotropin subunit beta 3 (P0DN86). Beta subunit of the human chorionic gonadotropin (hCG). hCG is a complex glycoprotein composed of two glycosylated subunits alpha and beta which are non-covalently associated.

This gene is a member of the glycoprotein hormone beta chain family and encodes the beta 5 subunit of chorionic gonadotropin (CG). Glycoprotein hormones are heterodimers consisting of a common alpha subunit and an unique beta subunit which confers biological specificity. CG is produced by the trophoblastic cells of the placenta and stimulates the ovaries to synthesize the steroids that are essential for the maintenance of pregnancy. The beta subunit of CG is encoded by 6 genes which are arranged in tandem and inverted pairs on chromosome 19q13.3 and contiguous with the luteinizing hormone beta subunit gene.

Source: NCBI Gene 93659 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 36 total
• MANE Select transcript: NM_033043

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:16452
Approved symbol	CGB5
Name	chorionic gonadotropin subunit beta 5
Location	19q13.33
Locus type	gene with protein product
Status	Approved
Aliases	HCG
Ensembl gene	ENSG00000189052
Ensembl biotype	protein_coding
OMIM	608825
Entrez	93659

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000301408

RefSeq mRNA: 1 — MANE Select: NM_033043 NM_033043

CCDS: CCDS12752

Canonical transcript exons

ENST00000301408 — 3 exons

Exon	Start	End
ENSE00002467366	49043848	49044224
ENSE00002511861	49044577	49044744
ENSE00002536246	49044980	49045311

Expression profiles

Bgee: expression breadth broad, 47 present calls, max score 81.82.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 1.7818 / max 716.0495, expressed in 113 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
176922	1.4496	110
176923	0.3322	4

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
placenta	UBERON:0001987	81.82	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	74.28	gold quality
pituitary gland	UBERON:0000007	53.91	gold quality
adenohypophysis	UBERON:0002196	52.32	gold quality
duodenum	UBERON:0002114	44.82	gold quality
colonic epithelium	UBERON:0000397	37.20	gold quality
ventricular zone	UBERON:0003053	36.48	gold quality
cortical plate	UBERON:0005343	36.47	gold quality
bone marrow cell	CL:0002092	36.16	gold quality
embryo	UBERON:0000922	35.49	silver quality
ganglionic eminence	UBERON:0004023	35.49	gold quality
muscle tissue	UBERON:0002385	35.42	gold quality
left testis	UBERON:0004533	34.79	gold quality
body of pancreas	UBERON:0001150	34.78	gold quality
pancreas	UBERON:0001264	33.83	gold quality
testis	UBERON:0000473	33.79	gold quality
smooth muscle tissue	UBERON:0001135	33.63	gold quality
skeletal muscle tissue	UBERON:0001134	33.38	gold quality
right testis	UBERON:0004534	33.18	gold quality
muscle of leg	UBERON:0001383	33.09	gold quality
bone marrow	UBERON:0002371	33.06	gold quality
gastrocnemius	UBERON:0001388	32.96	gold quality
descending thoracic aorta	UBERON:0002345	32.80	gold quality
right adrenal gland	UBERON:0001233	32.45	gold quality
skin of abdomen	UBERON:0001416	32.38	gold quality
zone of skin	UBERON:0000014	32.24	gold quality
hindlimb stylopod muscle	UBERON:0004252	32.15	gold quality
skin of leg	UBERON:0001511	32.10	gold quality
right adrenal gland cortex	UBERON:0035827	32.04	silver quality
olfactory segment of nasal mucosa	UBERON:0005386	31.09	gold quality

Single-cell (SCXA)

Detected in 8 experiment(s), a significant marker in 6.

Experiment	Marker?	Max mean expression
E-MTAB-7407	yes	61793.51
E-HCAD-24	yes	6071.94
E-MTAB-10018	yes	3226.83
E-HCAD-23	yes	2016.16
E-MTAB-8221	yes	102.00
E-HCAD-5	yes	29.23
E-MTAB-8060	no	47706.31
E-ANND-3	no	0.64

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): MTA3

Literature-anchored findings (GeneRIF, showing 31)

• The ISOBM TD-7 Workshop on hCG and related molecules. Towards user-oriented standardization of pregnancy and tumor diagnosis (PMID:11893904)
• Two closely spaced Ets-2 binding sites in the proximal promoter of the human chorionic gonadotropin beta5 (hCGbeta5) gene constitute a major enhancer for hCGbeta gene expression in JAr and JEG-3 human choriocarcinoma cells and in mouse NIH3T3 cells. (PMID:12511603)
• Agonists and antagonists will require the presence of other portions of hCGbeta in addition to the determinant loop/seat belt. (PMID:12914533)
• Increasing concentrations of Sp1, Sp3, and AP-2alpha enhance transcription of CGbeta in differentiating term trophoblasts, whereas a different combination of factors may control expression in early placentas. (PMID:14715707)
• OKL38 may function as an effector for human chorionic gonadotropin protection against mammary carcinogenesis. (PMID:15217983)
• The aim of the present investigation was to determine the expression pattern of human chorionic gonadotropin gene(hCG)and especially its beta-subunit in ovarian cancer tissue. (PMID:15253136)
• HCG-beta gene was found in patients with ovarian carcinoma, whereas noncancerous tissue demonstrated lack of the hormone expression. (PMID:15285305)
• Expression of hCGbeta correlates with specific infiltrative characteristics and is associated with higher VEGF expression (PMID:15309632)
• hCG up-regulating wnt7b and wnt5b could contribute to pregnancy-induced breast cancer in humans (PMID:17510243)
• compared the human (45,165 bp) and chimpanzee (39,876 bp) LHB/CGB regions and hereby present evidence for structural variation resulting in discordant number of CGB genes (6 in human, 5 in chimpanzee) (PMID:18606016)
• carriers of minor alleles of CGB had a reduced risk of recurrent miscarriage (PMID:18782867)
• hCGbeta V79M polymorphism is absent or extremely rare in Mexican Mestizo women. (PMID:19002615)
• Three single nucleotide polymorphisms in CGB5 and CSH1 genes were genotyped for 844 offspring of the cases and controls. Maternal breast cancer risk did not significantly differ by the offspring’s carrier status of the three SNPs. (PMID:19047151)
• Monochorionic twins have a significantly lower serum free beta-hCG (beta human chorionic gonadotropin) and a significantly lower PAPP-A(pregnancy-associated plasma protein A) compared to dichorionic (PMID:19173346)
• Our finding may represent a novel methylation allelic polymorphism or gain of imprinting in CGB5 promoter leading to expressional silencing of paternal alleles and increasing susceptibility to pregnancy loss. (PMID:20962020)
• PGDH activity was low before the ovulatory hCG stimulus, peaked 12-24 h after hCG, and was low again 36 h after hCG administration. (PMID:21167905)
• the accumulated data indicate that only mutations with neutral or mild functional consequences might be tolerated in the major hCG-beta genes CGB5 and CGB8. (PMID:22554618)
• Serum hCG concentrations were negatively associated with maternal prepregnancy body mass index. (PMID:22769733)
• Carriage of particular variants in the promoter of the CGB5 gene seems to protect against recurrent miscarriage. (PMID:23499152)
• Down-regulation of MTA3 and up-regulation of CGB5 and Snail are associated with preeclampsia. (PMID:23510993)
• The effect of human chorionic gonadotropin (hCG), an LH receptor agonist, on APP beta-cleavage in the SH-SY5Y neuroblastoma cell line. (PMID:23812658)
• This study showed a link between low maternal serum hCG levels and cryptorchidism in boys from uncomplicated pregnancy. (PMID:25064170)
• Genetic variation within the CGB5 gene is associated with recurrent spontaneous abortion risk in Chinese women. (PMID:25193288)
• TGF-beta enhances hCG-beta expression in glioblastoma. (PMID:25300619)
• Elevated serum human chorionic gonadotropin is associated with germ-cell tumours. (PMID:25456363)
• Data indicate the diagnostic criteria of chorionic gonadotropin beta subunit (beta-hCG) and alpha-Fetoprotein (alphaFP) in CSF and serum, which may advance the early and formal diagnosis of intracranial germ cell tumors (ICGCTs). (PMID:26968839)
• in mole pregnancy, levels at baseline, first, second, and third weeks post-evacuation predict persistent disease (PMID:28093002)
• CGB5, INHBA and TRAJ19 Hold Prognostic Potential as Immune Genes for Patients with Gastric Cancer. (PMID:35624327)
• Associations between nausea and vomiting in pregnancy, disgust sensitivity, and first-trimester maternal serum free beta-hCG and PAPP-A. (PMID:37062114)
• Human Chorionic Gonadotropin Regulates the Smad Signaling Pathway by Antagonizing TGF-beta in Giant Cell Tumor of Bone. (PMID:38214358)
• Human chorionic gonadotrophin indirectly activates peripheral gammadeltaT cells to produce interleukin-10 during early pregnancy. (PMID:38270320)

Cross-species orthologs

1 orthologs

Organism	Symbol	Gene ID
drosophila_melanogaster	Gpb5	FBGN0063368

Paralogs (9): CGB2 (ENSG00000104818), LHB (ENSG00000104826), CGB3 (ENSG00000104827), FSHB (ENSG00000131808), TSHB (ENSG00000134200), GPHB5 (ENSG00000179600), CGB7 (ENSG00000196337), CGB8 (ENSG00000213030), CGB1 (ENSG00000267631)

Protein

Protein identifiers

Choriogonadotropin subunit beta 3 — P0DN86 (reviewed: P0DN86)

Alternative names: Choriogonadotropin subunit beta, Chorionic gonadotropin chain beta

All UniProt accessions (2): A0A0F7RQP8, P0DN86

UniProt curated annotations — full annotation on UniProt →

Function. Beta subunit of the human chorionic gonadotropin (hCG). hCG is a complex glycoprotein composed of two glycosylated subunits alpha and beta which are non-covalently associated. The alpha subunit is identical to those in the pituitary gonadotropin hormones (LH, FSH and TSH). The beta subunits are distinct in each of the hormones and confer receptor and biological specificity. Has an essential role in pregnancy and maternal adaptation. Stimulates the ovaries to synthesize the steroids that are essential for the maintenance of pregnancy.

Subunit / interactions. Heterodimer of a common alpha chain identical in LH, FSH, TSH and HCG and a unique beta chain distinct in each of the hormones.

Subcellular location. Secreted.

Tissue specificity. High expression in the placenta throughout pregnancy.

Miscellaneous. Encoded by a cluster of genes that have evolved by duplication from LHB. HCG-beta is encoded by six non-allelic genes (CGB) clustered on chromosome 19q13.3 and named CGB1, CGB2, CGB3, CGB5, CGB7 and CGB8. Two specific hCGb proteins that differ by three amino acids in positions 2,4 and 117 have been described: type 1 (CGB7) and type 2 (CGB3, CGB5, CGB8). The CGB gene first arose in the common ancestor of the anthropoid primates.

Similarity. Belongs to the glycoprotein hormones subunit beta family.

Isoforms (2)

UniProt ID	Names	Canonical?
P0DN86-1	1	yes
P0DN86-2	2

RefSeq proteins (1): NP_149032* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001545	Gonadotropin_bsu	Family
IPR006208	Glyco_hormone_CN	Domain
IPR018245	Gonadotropin_bsu_CS	Conserved_site
IPR029034	Cystine-knot_cytokine	Homologous_superfamily

Pfam: PF00007

UniProt features (37 total): sequence variant 9, disulfide bond 6, strand 6, glycosylation site 6, sequence conflict 4, signal peptide 1, chain 1, splice variant 1, region of interest 1, compositionally biased region 1, turn 1

Structure

Experimental structures (PDB)

7 structures.

PDB	Method	Resolution (Å)
1HCN	X-RAY DIFFRACTION	2.6
9RHU	ELECTRON MICROSCOPY	2.65
1HRP	X-RAY DIFFRACTION	3
7FIH	ELECTRON MICROSCOPY	3.2
1QFW	X-RAY DIFFRACTION	3.5
7FIG	ELECTRON MICROSCOPY	3.9
7FII	ELECTRON MICROSCOPY	4.3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P0DN86-F1	79.10	0.47

Antibody-complex structures (SAbDab): 2 — 1QFW, 7FIG

Functional residue map

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

Disulfide bonds (6): 29–77, 43–92, 46–130, 54–108, 58–110, 113–120

Glycosylation sites (6): 33, 50, 141, 147, 152, 158

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-209822	Glycoprotein hormones
R-HSA-8866910	TFAP2 (AP-2) family regulates transcription of growth factors and their receptors

MSigDB gene sets: 11 (showing top): GGGTGGRR_PAX4_03, LU_EZH2_TARGETS_UP, EGR_Q6, REACTOME_PEPTIDE_HORMONE_METABOLISM, REACTOME_TRANSCRIPTIONAL_REGULATION_BY_THE_AP_2_TFAP2_FAMILY_OF_TRANSCRIPTION_FACTORS, REACTOME_TFAP2_AP_2_FAMILY_REGULATES_TRANSCRIPTION_OF_GROWTH_FACTORS_AND_THEIR_RECEPTORS, ZFP3_TARGET_GENES, ZNF92_TARGET_GENES, chr19q13, REACTOME_RNA_POLYMERASE_II_TRANSCRIPTION, REACTOME_PEPTIDE_HORMONE_BIOSYNTHESIS

GO Biological Process (6): apoptotic process (GO:0006915), signal transduction (GO:0007165), G protein-coupled receptor signaling pathway (GO:0007186), cell-cell signaling (GO:0007267), female gamete generation (GO:0007292), hormone-mediated signaling pathway (GO:0009755)

GO Molecular Function (3): hormone activity (GO:0005179), signaling receptor binding (GO:0005102), protein binding (GO:0005515)

GO Cellular Component (4): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), cytoplasm (GO:0005737), pituitary gonadotropin complex (GO:0061696)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Peptide hormone biosynthesis	1
Transcriptional regulation by the AP-2 (TFAP2) family of transcription factors	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cell communication	2
signaling	2
signal transduction	2
cellular anatomical structure	2
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
cellular process	1
regulation of cellular process	1
cellular response to stimulus	1
G protein-coupled receptor activity	1
gamete generation	1
cellular response to hormone stimulus	1
receptor ligand activity	1
protein binding	1
binding	1
intracellular anatomical structure	1
extracellular protein-containing complex	1

Protein interactions and networks

STRING

0 interactions, top by confidence (×1000):

IntAct

10 interactions, top by confidence:

A	B	Type	Score
CGA	CGB5	psi-mi:“MI:0407”(direct interaction)	0.590
CGA	CGB5	psi-mi:“MI:0915”(physical association)	0.590
CGB5	SMCP	psi-mi:“MI:0915”(physical association)	0.560
CGB5	GPHA2	psi-mi:“MI:0915”(physical association)	0.370
CGB5	CFTR	psi-mi:“MI:0915”(physical association)	0.370
CGB5	IGSF3	psi-mi:“MI:0914”(association)	0.350
CGB5	DNAJC5	psi-mi:“MI:2364”(proximity)	0.270
CGB5	SMCP	psi-mi:“MI:0915”(physical association)	0.000

ESM2 similar proteins: A6NKQ9, B1AWI6, G7PWZ3, I6M4H4, O09108, O46482, O46483, O46641, O77805, O77835, P01229, P01230, P01231, P01232, P04651, P07434, P08751, P0DN86, P0DN87, P17490, P19794, P27767, P30984, P43021, P45646, P45657, P51500, Q04997, Q1L6U9, Q2Q1P0, Q2Q1P1, Q2Q1P2, Q3HRV3, Q3S2X5, Q6EV78, Q6HA10, Q6NT52, Q6PX77, Q7ZZV4, Q8CB67

Diamond homologs: A1BN60, A1BN61, A6NKQ9, O09108, O13050, O46430, O46482, O46483, O46641, O57340, O73824, O77805, O77835, P01222, P01223, P01224, P01225, P01226, P01227, P01228, P01229, P01230, P01231, P01232, P01235, P04651, P04652, P04837, P07434, P07732, P08751, P0DN86, P0DN87, P10256, P10257, P12656, P12837, P18427, P19794, P25330

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	29
Likely benign	4
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

292 predictions. Top by Δscore:

Variant	Effect	Δscore
19:49044571:TCCCA:T	acceptor_loss	1.0000
19:49044572:CCCA:C	acceptor_loss	1.0000
19:49044573:CCA:C	acceptor_loss	1.0000
19:49044574:CA:C	acceptor_loss	1.0000
19:49044575:A:C	acceptor_loss	1.0000
19:49044575:AG:A	acceptor_gain	1.0000
19:49044576:GG:G	acceptor_gain	1.0000
19:49044745:G:GG	donor_gain	1.0000
19:49044745:G:T	donor_loss	1.0000
19:49044746:T:A	donor_loss	1.0000
19:49044575:A:AG	acceptor_gain	0.9900
19:49044575:AGG:A	acceptor_gain	0.9900
19:49044575:AGGG:A	acceptor_gain	0.9900
19:49044576:G:GG	acceptor_gain	0.9900
19:49044576:GGG:G	acceptor_gain	0.9900
19:49044576:GGGG:G	acceptor_gain	0.9900
19:49044576:GGGGC:G	acceptor_gain	0.9900
19:49044740:CCATG:C	donor_gain	0.9900
19:49044743:TG:T	donor_gain	0.9900
19:49044744:GG:G	donor_gain	0.9900
19:49044747:GAGCT:G	donor_loss	0.9900
19:49044969:AC:A	acceptor_gain	0.9800
19:49044970:C:G	acceptor_gain	0.9800
19:49044741:CATG:C	donor_gain	0.9700
19:49044742:ATG:A	donor_gain	0.9700
19:49044967:ACAC:A	acceptor_gain	0.9700
19:49044969:ACG:A	acceptor_gain	0.9700
19:49044970:C:CA	acceptor_gain	0.9700
19:49044744:GGT:G	donor_gain	0.9600
19:49044745:GTG:G	donor_gain	0.9600

AlphaMissense

1048 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000188968 (19:49043932 G>A,C,T), RS1000919603 (19:49043061 A>T), RS1001093950 (19:49042904 G>A,C,T), RS1001308378 (19:49045660 G>A), RS1002935764 (19:49042106 G>A), RS1002936208 (19:49044761 C>A,T), RS1003273379 (19:49043967 G>A,C), RS1003431350 (19:49045468 T>C,G), RS1005370839 (19:49042604 A>C), RS1007042884 (19:49042228 T>C,G), RS1007172347 (19:49044279 A>C,G), RS1007182154 (19:49044397 T>C), RS1007374091 (19:49045725 T>A,C), RS1008423441 (19:49042079 CTGAGAGGTGCTCTGA>C), RS1008839344 (19:49043417 C>G,T)

Disease associations

OMIM: gene MIM:608825 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

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

15 total (human), top 15 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
ethyl-p-hydroxybenzoate	decreases expression	1
beta-lapachone	increases expression	1
sodium arsenite	increases expression	1
erucylphospho-N,N,N-trimethylpropylammonium	increases expression	1
abrine	increases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Pioglitazone	increases expression	1
Atrazine	increases expression	1
Benzo(a)pyrene	increases methylation, decreases methylation	1
Endosulfan	decreases expression	1
Estradiol	affects cotreatment, increases expression	1
Plant Extracts	affects cotreatment, decreases expression	1
Valproic Acid	increases methylation	1
Okadaic Acid	increases expression	1
beta-Naphthoflavone	decreases expression	1

Clinical trials (associated diseases)

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