CHP2

Summary

CHP2 (calcineurin like EF-hand protein 2, HGNC:24927) is a protein-coding gene on chromosome 16p12.2, encoding Calcineurin B homologous protein 2 (O43745). Functions as an integral cofactor in cell pH regulation by controlling plasma membrane-type Na(+)/H(+) exchange activity.

This gene product is a small calcium-binding protein that regulates cell pH by controlling plasma membrane-type Na+/H+ exchange activity. This protein shares sequence similarity with calcineurin B and can bind to and stimulate the protein phosphatase activity of calcineurin A (CnA) and functions in the calcineurin/NFAT (nuclear factor of activated T cells) signaling pathway. Another member of the CHP subfamily, Calcineurin B homologous protein 1, is located on Chromosome 15 and is an inhibitor of calcineurin activity and has a genetic phenotype associated with Parkinson’s Disease (OMIM:606988). This gene was initially identified as a tumor-associated antigen and was previously referred to as Hepatocellular carcinoma-associated antigen 520.

Source: NCBI Gene 63928 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 45 total
• MANE Select transcript: NM_022097

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:24927
Approved symbol	CHP2
Name	calcineurin like EF-hand protein 2
Location	16p12.2
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000166869
Ensembl biotype	protein_coding
Entrez	63928

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 5 protein_coding

ENST00000300113, ENST00000871594, ENST00000871595, ENST00000871596, ENST00000871597

RefSeq mRNA: 1 — MANE Select: NM_022097 NM_022097

CCDS: CCDS10617

Canonical transcript exons

ENST00000300113 — 7 exons

Exon	Start	End
ENSE00001175689	23757201	23757323
ENSE00001175695	23756388	23756449
ENSE00001175699	23756063	23756193
ENSE00001175702	23755847	23755927
ENSE00001175706	23755661	23755733
ENSE00001175714	23755026	23755116
ENSE00001290337	23757530	23758935

Expression profiles

Bgee: expression breadth ubiquitous, 180 present calls, max score 99.17.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.6402 / max 307.2072, expressed in 63 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
153171	0.4123	27
153170	0.0864	12
153168	0.0591	30
153169	0.0293	7
153175	0.0174	6
153172	0.0169	10
153174	0.0164	7
153173	0.0024	1

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
mucosa of transverse colon	UBERON:0004991	99.17	gold quality
ileal mucosa	UBERON:0000331	98.93	gold quality
rectum	UBERON:0001052	97.95	gold quality
upper leg skin	UBERON:0004262	96.64	gold quality
jejunal mucosa	UBERON:0000399	96.22	gold quality
skin of abdomen	UBERON:0001416	95.54	gold quality
duodenum	UBERON:0002114	95.38	gold quality
colonic mucosa	UBERON:0000317	95.17	gold quality
upper arm skin	UBERON:0004263	95.13	gold quality
skin of hip	UBERON:0001554	94.71	gold quality
skin of leg	UBERON:0001511	94.26	gold quality
mucosa of sigmoid colon	UBERON:0004993	94.14	gold quality
zone of skin	UBERON:0000014	93.95	gold quality
small intestine Peyer’s patch	UBERON:0003454	91.01	gold quality
small intestine	UBERON:0002108	90.66	gold quality
transverse colon	UBERON:0001157	89.32	gold quality
nipple	UBERON:0002030	82.77	gold quality
mammalian vulva	UBERON:0000997	82.16	gold quality
intestine	UBERON:0000160	81.92	gold quality
tibial nerve	UBERON:0001323	80.96	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	79.48	gold quality
large intestine	UBERON:0000059	79.01	gold quality
colon	UBERON:0001155	78.38	gold quality
jejunum	UBERON:0002115	77.84	gold quality
colonic epithelium	UBERON:0000397	77.76	gold quality
epithelium of bronchus	UBERON:0002031	77.71	gold quality
palpebral conjunctiva	UBERON:0001812	77.06	gold quality
bronchus	UBERON:0002185	76.40	gold quality
trigeminal ganglion	UBERON:0001675	76.01	gold quality
bronchial epithelial cell	CL:0002328	75.38	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-CURD-114	yes	109.38
E-GEOD-125970	yes	16.49
E-MTAB-8410	yes	13.86
E-ANND-3	yes	9.68

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

64 targeting CHP2, 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-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-568	99.98	69.86	2084
HSA-MIR-3617-3P	99.98	67.86	918
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-1236-3P	99.94	68.04	1695
HSA-MIR-6753-3P	99.93	66.57	637
HSA-MIR-7107-3P	99.93	66.73	627
HSA-MIR-106A-5P	99.90	73.94	2683
HSA-MIR-17-5P	99.89	73.83	2665
HSA-MIR-106B-5P	99.88	74.72	2795
HSA-MIR-20A-5P	99.88	74.76	2769
HSA-MIR-20B-5P	99.88	74.01	2621
HSA-MIR-519D-3P	99.88	73.97	2607
HSA-MIR-526B-3P	99.88	74.06	2587
HSA-MIR-93-5P	99.88	73.98	2606
HSA-MIR-944	99.82	70.85	3042
HSA-MIR-3121-3P	99.82	71.96	3630
HSA-MIR-4760-5P	99.80	69.88	1619
HSA-MIR-3913-3P	99.74	66.53	938
HSA-MIR-2116-3P	99.74	64.32	889
HSA-MIR-6505-5P	99.73	69.25	1595
HSA-MIR-8061	99.63	69.44	1411
HSA-MIR-4663	99.62	65.33	957
HSA-MIR-4524B-5P	99.57	71.68	1195
HSA-MIR-4524A-5P	99.57	71.73	1193
HSA-MIR-4276	99.56	67.66	2514
HSA-MIR-4251	99.40	69.19	3363

Literature-anchored findings (GeneRIF, showing 7)

• These findings suggest that CHP serves as an obligatory subunit that is required both for supporting the basic activity and regulating the pH-sensing of NHE1 via interactions between distinct parts of these proteins. (PMID:16710297)
• overexpression of the CHP2 gene affects the biological behavior of ovarian cancer cell line OVCAR3 and is one of key mechanisms for ovarian carcinoma progression (PMID:17708351)
• chp2 expression in leukemia primary cells and leukemia cell lines is significantly increased. (PMID:18718049)
• CHP2 expression is significantly downregulated in human masticatory mucosa during wound healing (PMID:28005267)
• we demonstrated that overexpression of CHP2 enhanced G1-S phase transition mediated by AKT activation, which subsequently induced phosphorylation and inactivation of FOXO3a in breast cancer cells. (PMID:29967111)
• the data support the tumor-promoting potential of aberrant calcineurin B homologous protein 2 expression and position calcineurin B homologous protein 2 as a potential therapeutic target for the treatment of non-small cell lung cancer. (PMID:32686600)
• Involvement of CHP2 in the Development of Non-Small Cell Lung Cancer and Patients’ Poor Prognosis. (PMID:33030853)

Cross-species orthologs

9 orthologs

Organism	Symbol	Gene ID
mus_musculus	Chp2	ENSMUSG00000030865
rattus_norvegicus	Chp2	ENSRNOG00000019112
drosophila_melanogaster	CG32812	FBGN0025642
drosophila_melanogaster	Cib2	FBGN0034558
drosophila_melanogaster	elm	FBGN0037358
drosophila_melanogaster	CG14362	FBGN0038186
caenorhabditis_elegans	calm-1	WBGENE00009260
caenorhabditis_elegans		WBGENE00014109
caenorhabditis_elegans		WBGENE00019108

Paralogs (8): TESC (ENSG00000088992), CIB2 (ENSG00000136425), CIB3 (ENSG00000141977), CIB4 (ENSG00000157884), CIB1 (ENSG00000185043), CHP1 (ENSG00000187446), PPP3R2 (ENSG00000188386), PPP3R1 (ENSG00000221823)

Protein

Protein identifiers

Calcineurin B homologous protein 2 — O43745 (reviewed: O43745)

Alternative names: Hepatocellular carcinoma-associated antigen 520

All UniProt accessions (1): O43745

UniProt curated annotations — full annotation on UniProt →

Function. Functions as an integral cofactor in cell pH regulation by controlling plasma membrane-type Na(+)/H(+) exchange activity. Binds to and activates SLC9A1/NHE1 in a serum-independent manner, thus increasing pH and protecting cells from serum deprivation-induced death. Also plays a role in the regulation of cell proliferation and tumor growth by increasing the phosphatase activity of PPP3CA in a calcium-dependent manner. Activator of the calcineurin/NFAT signaling pathway. Involved in the cytoplasmic translocation of the transcription factor NFATC3 to the nucleus.

Subunit / interactions. Interacts with PPP3CA. Interacts with SLC9A1/NHE1; the interaction occurs in a calcium-dependent manner.

Subcellular location. Nucleus. Cytoplasm. Cell membrane.

Tissue specificity. Expressed in malignantly transformed cells but not detected in normal tissues.

Similarity. Belongs to the calcineurin regulatory subunit family. CHP subfamily.

RefSeq proteins (1): NP_071380* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002048	EF_hand_dom	Domain
IPR011992	EF-hand-dom_pair	Homologous_superfamily
IPR018247	EF_Hand_1_Ca_BS	Binding_site
IPR051875	Calcineurin_B_homologous	Family

Pfam: PF13202, PF13499

UniProt features (42 total): helix 13, binding site 9, mutagenesis site 5, domain 4, turn 3, strand 2, initiator methionine 1, chain 1, modified residue 1, lipid moiety-binding region 1, sequence variant 1, short sequence motif 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
2BEC	X-RAY DIFFRACTION	2.7

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O43745-F1	86.86	0.63

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 (9): 130; 135; 165; 167; 169; 176; 124; 126; 128

Post-translational modifications (2): 27, 2

Mutagenesis-validated functional residues (5):

Position	Phenotype
50	does not reduce calcium-binding.
82	does not reduce calcium-binding.
135	reduces calcium-binding. inhibits calcium-binding and cell membrane localization; when associated with a-176.
137–148	localizes in the nucleus and increases cell proliferation.
176	reduces calcium-binding. inhibits calcium-binding and cell membrane localization; when associated with a-135.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 150 (showing top): GOBP_REGULATION_OF_CALCIUM_MEDIATED_SIGNALING, GOBP_INTRACELLULAR_PROTEIN_TRANSPORT, GOBP_REGULATION_OF_PHOSPHATASE_ACTIVITY, JAEGER_METASTASIS_DN, KEGG_MAPK_SIGNALING_PATHWAY, GOBP_POSITIVE_REGULATION_OF_INTRACELLULAR_PROTEIN_TRANSPORT, GOBP_POSITIVE_REGULATION_OF_PROTEIN_LOCALIZATION, GOBP_ESTABLISHMENT_OF_PROTEIN_LOCALIZATION_TO_ORGANELLE, GOBP_RESPONSE_TO_METAL_ION, GOBP_POSITIVE_REGULATION_OF_INTRACELLULAR_TRANSPORT, GOBP_NUCLEAR_TRANSPORT, GOBP_POSITIVE_REGULATION_OF_PROTEIN_LOCALIZATION_TO_NUCLEUS, GOBP_POSITIVE_REGULATION_OF_CATALYTIC_ACTIVITY, GOBP_REGULATION_OF_HYDROLASE_ACTIVITY, GOBP_POSITIVE_REGULATION_OF_CALCIUM_MEDIATED_SIGNALING

GO Biological Process (9): positive regulation of cell population proliferation (GO:0008284), positive regulation of phosphatase activity (GO:0010922), protein transport (GO:0015031), positive regulation of protein import into nucleus (GO:0042307), positive regulation of transcription by RNA polymerase II (GO:0045944), positive regulation of calcineurin-NFAT signaling cascade (GO:0070886), cellular response to calcium ion (GO:0071277), regulation of protein import into nucleus (GO:0042306), regulation of calcineurin-NFAT signaling cascade (GO:0070884)

GO Molecular Function (3): calcium ion binding (GO:0005509), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (7): nucleus (GO:0005634), nucleoplasm (GO:0005654), nucleolus (GO:0005730), cytoplasm (GO:0005737), cytosol (GO:0005829), plasma membrane (GO:0005886), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
protein import into nucleus	2
calcineurin-NFAT signaling cascade	2
nuclear lumen	2
cell population proliferation	1
regulation of cell population proliferation	1
positive regulation of cellular process	1
regulation of phosphatase activity	1
phosphatase activity	1
positive regulation of dephosphorylation	1
positive regulation of hydrolase activity	1
transport	1
intracellular protein localization	1
establishment of protein localization	1
regulation of protein import into nucleus	1
positive regulation of nucleocytoplasmic transport	1
positive regulation of intracellular protein transport	1
positive regulation of protein localization to nucleus	1
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
positive regulation of DNA-templated transcription	1
regulation of calcineurin-NFAT signaling cascade	1
positive regulation of calcineurin-mediated signaling	1
response to calcium ion	1
cellular response to metal ion	1
regulation of intracellular protein transport	1
regulation of nucleocytoplasmic transport	1
regulation of protein localization to nucleus	1
regulation of calcineurin-mediated signaling	1
metal ion binding	1
binding	1
cation binding	1
intracellular membrane-bounded organelle	1
intracellular membraneless organelle	1
intracellular anatomical structure	1
cytoplasm	1
membrane	1
cell periphery	1

Protein interactions and networks

STRING

1123 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CHP2	C9orf78	Q9NZ63	390
CHP2	NKX2-8	O15522	362
CHP2	MS4A12	Q9NXJ0	323
CHP2	CPS1	P31327	320
CHP2	SLC9A1	P19634	301
CHP2	MAGEC2	Q9UBF1	300
CHP2	PSD3	Q9NYI0	287
CHP2	TPX2	Q9ULW0	257
CHP2	NFATC3	Q12968	253
CHP2	PRKAR2A	P13861	246
CHP2	H3BTC1	H3BTC1	228
CHP2	IRS4	O14654	227
CHP2	MUTYH	Q9UIF7	226
CHP2	AIFM1	O95831	223
CHP2	USP16	Q9Y5T5	216

IntAct

15 interactions, top by confidence:

A	B	Type	Score
CHP2	SLC9A1	psi-mi:“MI:0407”(direct interaction)	0.780
CHP2	MDFI	psi-mi:“MI:0915”(physical association)	0.560
	CHP2	psi-mi:“MI:0407”(direct interaction)	0.560
EBF2	LILRA5	psi-mi:“MI:0914”(association)	0.350
CHP2	PCDH7	psi-mi:“MI:0914”(association)	0.350
SLC9A2	MEIOC	psi-mi:“MI:0914”(association)	0.350
SLC9A3	ESYT3	psi-mi:“MI:0914”(association)	0.350
SLC9A5	NBAS	psi-mi:“MI:0914”(association)	0.350
CHP2	MDFI	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (19): CHP2 (Proximity Label-MS), SLC9A1 (Reconstituted Complex), SLC9A2 (Reconstituted Complex), SLC9A3 (Reconstituted Complex), SLC9A4 (Reconstituted Complex), SLC9A5 (Reconstituted Complex), CHP2 (Affinity Capture-Western), CHP2 (Affinity Capture-Western), CHP2 (Two-hybrid), C17orf70 (Affinity Capture-MS), SLC9A1 (Affinity Capture-MS), ASAH1 (Affinity Capture-MS), CHP2 (Affinity Capture-MS), PCDH7 (Affinity Capture-MS), FAM160B1 (Affinity Capture-MS)

ESM2 similar proteins: A0AVX7, A2VEI2, F4J0W4, O43745, O70200, O73761, O73762, P04354, P04467, P05937, P07171, P12658, P22728, P41044, P43080, P43081, P46065, P51177, P55008, P61022, P61023, P79880, P81076, Q0V9B1, Q1LWZ0, Q298L5, Q3KQ77, Q3SYS6, Q3T024, Q4R760, Q4V7T8, Q5R4V1, Q5R7F0, Q5TM25, Q5U554, Q5ZM44, Q6P8Y1, Q810D1, Q8IMX7, Q8R426

Diamond homologs: A0AVX7, O43745, P42322, P61022, P61023, Q0V9B1, Q3SYS6, Q54MF3, Q5R7F0, Q5U554, Q5ZM44, Q6FLU4, Q757B7, Q810D1, Q874T7, Q96BS2, Q99653, Q9D869, Q9JKL5, A0A509AFG4, A9JTH1, B3DLU1, B3VSB7, B5FZ84, C7A276, G5EDN6, O75838, O81223, O81445, P04464, P05419, P06707, P06708, P0CM54, P0CM55, P25296, P28470, P29104, P29105, P29291

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	41
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1044 predictions. Top by Δscore:

Variant	Effect	Δscore
16:23755113:GGCT:G	donor_gain	1.0000
16:23755114:GCTG:G	donor_gain	1.0000
16:23755117:G:GG	donor_gain	1.0000
16:23755659:A:AG	acceptor_gain	1.0000
16:23755660:G:GG	acceptor_gain	1.0000
16:23755713:GAA:G	donor_gain	1.0000
16:23755845:A:AG	acceptor_gain	1.0000
16:23755846:G:GG	acceptor_gain	1.0000
16:23755846:GCCGC:G	acceptor_gain	1.0000
16:23755909:A:T	donor_gain	1.0000
16:23755923:GATGG:G	donor_gain	1.0000
16:23755926:GG:G	donor_gain	1.0000
16:23755927:GG:G	donor_gain	1.0000
16:23755928:G:GG	donor_gain	1.0000
16:23755928:GT:G	donor_loss	1.0000
16:23755929:T:G	donor_loss	1.0000
16:23756047:T:TA	acceptor_gain	1.0000
16:23756052:C:A	acceptor_gain	1.0000
16:23756060:CAG:C	acceptor_loss	1.0000
16:23756061:A:AG	acceptor_gain	1.0000
16:23756061:A:T	acceptor_loss	1.0000
16:23756061:AG:A	acceptor_gain	1.0000
16:23756062:G:GG	acceptor_gain	1.0000
16:23756062:GG:G	acceptor_gain	1.0000
16:23756062:GGA:G	acceptor_gain	1.0000
16:23756180:G:GT	donor_gain	1.0000
16:23756181:A:T	donor_gain	1.0000
16:23756189:TCACT:T	donor_gain	1.0000
16:23756192:CT:C	donor_gain	1.0000
16:23756192:CTG:C	donor_loss	1.0000

AlphaMissense

1305 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
16:23756393:T:C	F120L	0.998
16:23756395:T:A	F120L	0.998
16:23756395:T:G	F120L	0.998
16:23755696:T:C	F35L	0.997
16:23755698:C:A	F35L	0.997
16:23755698:C:G	F35L	0.997
16:23757315:T:C	F177L	0.996
16:23757317:C:A	F177L	0.996
16:23757317:C:G	F177L	0.996
16:23756186:A:C	K115N	0.995
16:23756186:A:T	K115N	0.995
16:23756427:T:C	I131T	0.995
16:23757316:T:C	F177S	0.995
16:23755697:T:C	F35S	0.994
16:23757262:G:C	R159P	0.994
16:23756088:T:C	F83L	0.993
16:23756090:T:A	F83L	0.993
16:23756090:T:G	F83L	0.993
16:23756109:T:C	F90L	0.993
16:23756111:T:A	F90L	0.993
16:23756111:T:G	F90L	0.993
16:23755886:C:A	N60K	0.992
16:23755886:C:G	N60K	0.992
16:23755903:T:C	I66T	0.992
16:23756184:A:G	K115E	0.991
16:23756427:T:G	I131S	0.991
16:23757276:G:C	A164P	0.991
16:23756080:T:C	F80S	0.990
16:23756089:T:C	F83S	0.989
16:23756103:G:C	A88P	0.989

dbSNP variants (sampled 300 via entrez): RS1000062972 (16:23753960 C>T), RS1000073115 (16:23753793 C>T), RS1000218504 (16:23753938 G>A), RS1000275916 (16:23758710 T>A), RS1000322693 (16:23759308 C>T), RS1000626262 (16:23759001 T>C), RS1000883545 (16:23754177 G>A), RS1001079621 (16:23754782 A>G), RS1001094735 (16:23759080 C>T), RS1001524623 (16:23754450 C>A,G,T), RS1001778500 (16:23758967 A>G), RS1001976656 (16:23754222 G>T), RS1002321085 (16:23754821 C>G,T), RS1002581411 (16:23755183 G>A,C), RS1002939355 (16:23755485 C>A)

Disease associations

OMIM: gene `` | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST011494_70	Daytime nap	2.000000e-09

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0007828	daytime rest measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

19 total (human), top 19 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
entinostat	increases expression, affects cotreatment	2
Valproic Acid	affects expression, increases expression	2
testosterone undecanoate	decreases expression	1
sodium arsenite	increases expression	1
butyraldehyde	increases expression	1
hydroquinone	decreases expression	1
pentanal	increases expression	1
tanespimycin	decreases expression, affects cotreatment	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
VER 155008	affects cotreatment, decreases expression	1
Air Pollutants	decreases expression, increases abundance	1
Benzo(a)pyrene	affects methylation, increases methylation	1
Diethylhexyl Phthalate	decreases expression	1
Formaldehyde	decreases expression	1
Nickel	decreases expression	1
Smoke	decreases expression, increases abundance	1
Testosterone	decreases expression	1
Tobacco Smoke Pollution	decreases expression	1

Clinical trials (associated diseases)

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