SPINK7

Summary

SPINK7 (serine peptidase inhibitor Kazal type 7, HGNC:24643) is a protein-coding gene on chromosome 5q32, encoding Serine protease inhibitor Kazal-type 7 (P58062). Probable serine protease inhibitor.

Predicted to enable serine-type endopeptidase inhibitor activity. Predicted to act upstream of or within inflammatory response and negative regulation of cytokine production involved in inflammatory response. Predicted to be located in extracellular space.

Source: NCBI Gene 84651 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 1 total
• MANE Select transcript: NM_032566

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:24643
Approved symbol	SPINK7
Name	serine peptidase inhibitor Kazal type 7
Location	5q32
Locus type	gene with protein product
Status	Approved
Aliases	ECG2, ECRG2
Ensembl gene	ENSG00000145879
Ensembl biotype	protein_coding
OMIM	617288
Entrez	84651

Gene structure

Transcript identifiers

Ensembl transcripts: 6 — 3 retained_intron, 2 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000274565, ENST00000504037, ENST00000514394, ENST00000514646, ENST00000523535, ENST00000523913

RefSeq mRNA: 1 — MANE Select: NM_032566 NM_032566

CCDS: CCDS4289

Canonical transcript exons

ENST00000274565 — 4 exons

Exon	Start	End
ENSE00000972773	148312423	148312544
ENSE00000972775	148314100	148314224
ENSE00003513760	148313374	148313399
ENSE00003672010	148315639	148315919

Expression profiles

Bgee: expression breadth ubiquitous, 163 present calls, max score 99.71.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 1.8251 / max 732.8404, expressed in 67 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
59311	1.8251	67

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
lower esophagus mucosa	UBERON:0035834	99.71	gold quality
gingiva	UBERON:0001828	99.16	gold quality
gingival epithelium	UBERON:0001949	99.04	gold quality
pharyngeal mucosa	UBERON:0000355	97.90	gold quality
esophagus mucosa	UBERON:0002469	96.30	gold quality
oral cavity	UBERON:0000167	96.27	gold quality
esophagus squamous epithelium	UBERON:0006920	95.06	gold quality
body of tongue	UBERON:0011876	93.10	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	92.45	gold quality
buccal mucosa cell	CL:0002336	92.37	gold quality
tongue	UBERON:0001723	86.92	gold quality
amniotic fluid	UBERON:0000173	84.08	gold quality
vagina	UBERON:0000996	82.24	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	78.23	gold quality
esophagus	UBERON:0001043	77.93	gold quality
superior surface of tongue	UBERON:0007371	77.59	gold quality
tonsil	UBERON:0002372	74.95	gold quality
ectocervix	UBERON:0012249	72.66	gold quality
skin of leg	UBERON:0001511	72.15	gold quality
mouth mucosa	UBERON:0003729	69.29	gold quality
mammalian vulva	UBERON:0000997	68.37	gold quality
penis	UBERON:0000989	67.91	gold quality
uterine cervix	UBERON:0000002	67.63	gold quality
zone of skin	UBERON:0000014	67.08	gold quality
corpus callosum	UBERON:0002336	66.35	gold quality
upper arm skin	UBERON:0004263	66.00	silver quality
skin of abdomen	UBERON:0001416	65.59	gold quality
minor salivary gland	UBERON:0001830	64.94	gold quality
pancreatic ductal cell	CL:0002079	64.54	silver quality
nasal cavity epithelium	UBERON:0005384	64.34	silver quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.39

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

27 targeting SPINK7, 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-6833-3P	100.00	70.63	3197
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-4697-3P	99.89	67.09	1123
HSA-MIR-5582-3P	99.86	72.48	4221
HSA-MIR-548AR-3P	99.85	71.26	3889
HSA-MIR-548AZ-3P	99.82	70.56	3549
HSA-MIR-548BC	99.82	70.61	3524
HSA-MIR-548E-3P	99.82	70.59	3514
HSA-MIR-548F-3P	99.82	70.59	3540
HSA-MIR-548A-3P	99.76	70.58	3524
HSA-MIR-4766-5P	99.75	69.23	2662
HSA-MIR-545-5P	99.66	70.18	2308
HSA-MIR-4316	99.37	65.75	1360
HSA-MIR-1272	99.34	68.79	878
HSA-MIR-661	99.09	65.94	2062
HSA-MIR-6506-5P	99.04	65.66	1386
HSA-MIR-382-3P	98.83	67.10	1074
HSA-MIR-619-5P	98.57	64.97	1988
HSA-MIR-5187-5P	98.54	67.94	952
HSA-MIR-135A-2-3P	98.40	66.74	442
HSA-MIR-135B-3P	98.40	67.35	426
HSA-MIR-4314	97.50	67.30	1369
HSA-MIR-6131	97.22	66.72	960
HSA-MIR-4714-5P	97.04	67.76	955
HSA-MIR-3192-5P	96.98	65.76	1926
HSA-MIR-4264	96.35	64.76	1480

Literature-anchored findings (GeneRIF, showing 21)

• Data suggest that the physical interaction of esophageal cancer related gene 2 (ECRG2) and metallothionein 2A (MT2A) may play an important role in the carcinogenesis of esophageal cancer. (PMID:12646258)
• Potential interaction partner for ECRG2 might be involved in regulation of cell proliferation and apoptosis and in various physiological processes. (PMID:12970870)
• Short tandem repeat polymorphism in a novel esophageal cancer-related gene (ECRG2) implicates susceptibility to esophageal cancer (PMID:14639608)
• Short tandem repeat polymorphism TCA3/TCA3 in exon 4 of ECRG2 is associated with poor relapse-free survival in surgically completely resected oral squamous cell carcinoma patients and might be a potential prognostic marker (PMID:17418617)
• results suggest that ECRG2 inhibits aggressiveness of cancer cell, possibly through the down-regulation of uPA/plasmin activity (PMID:17602171)
• genetically fixed short tandem repeat polymorphism TCA3/TCA3 in exon 4 of ECRG2 is associated with poor clinical outcome in surgically treated esophageal cancer patients and might be a potential prognostic marker (PMID:17693286)
• ECRG2 is important for ensuring centrosome duplication, spindle assembly checkpoint, and accurate chromosome segregation, and its depletion may contribute to chromosome instability and aneuploidy in human cancers. (PMID:18162463)
• the ECRG2 TCA (3)/TCA (4) genotype is associated with the risk of oesophageal carcinoma in a North Indian population. (PMID:18618216)
• uPA-binding loops of ECRG2 are in correspondence with the reactive site loops for binding of serine proteinase in turkey ovomucoid third domain (OMTKY3). (PMID:18824154)
• ECRG2 is involved in the regulation of cell migration/invasion through uPA/uPAR/beta1 integrin pathway. (PMID:19717562)
• ECRG2 regulates invasion/migration partly through ECM degradation and uPA/uPAR/FPRL1 pathway (PMID:19796867)
• ECRG2 is a novel member of the Kazal-type serine protease inhibitor family and may function as a tumor suppressor gene regulating the protease cascades during carcinogenesis and invasion of esophageal cancer. (PMID:21042721)
• miR-1322 can regulate ECRG2 in an allele-specific manner and that serum levels of miR-1322 can serve as a potential diagnostic biomarker for patients with ESCC. (PMID:22315007)
• Conformational study of ECRG2 using NMR. (PMID:22528291)
• Negative regulation of RNA-binding protein HuR by tumor-suppressor ECRG2 (PMID:26434587)
• ECRG2 in combination with cisplatin (DDP) can inhibit viability and induce apoptosis in esophageal cancer DDP-resistant cells, possibly via upregulation of p53 expression and downregulation of PCNA expression. (PMID:28348485)
• n cultured keratinocytes, SPINK7 mRNA expression was up-regulated by IL-17A together with IFNgamma (PMID:28852849)
• SPINK7 (serine peptidase inhibitor, kazal type 7), is part of the differentiation program of human esophageal epithelium. (PMID:29875205)
• ECRG2, a novel transcriptional target of p53, modulates cancer cell sensitivity to DNA damage. (PMID:32681017)
• ECRG2/SPINK7 is a novel pro-apoptotic target of p53, which is induced by DNA damage in a p53-dependent manner. (PMID:32681017)
• SPINK7 expression changes accompanied by HER2, P53 and RB1 can be relevant in predicting oral squamous cell carcinoma at a molecular level. (PMID:33767253)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Spink7	ENSMUSG00000060201
rattus_norvegicus	Spink7	ENSRNOG00000032873

Paralogs (5): SPINK2 (ENSG00000128040), SPINK14 (ENSG00000196800), SPINK9 (ENSG00000204909), SPINK13 (ENSG00000214510), SPINK8 (ENSG00000229453)

Protein

Protein identifiers

Serine protease inhibitor Kazal-type 7 — P58062 (reviewed: P58062)

Alternative names: Esophagus cancer-related gene 2 protein

All UniProt accessions (2): E5RFX6, P58062

UniProt curated annotations — full annotation on UniProt →

Function. Probable serine protease inhibitor.

Subcellular location. Secreted.

RefSeq proteins (1): NP_115955* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002350	Kazal_dom	Domain
IPR036058	Kazal_dom_sf	Homologous_superfamily
IPR050159	Kazal-type_SerProtInhib	Family

Pfam: PF00050

UniProt features (13 total): strand 4, disulfide bond 3, helix 2, signal peptide 1, chain 1, domain 1, site 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
2LEO	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P58062-F1	90.34	0.67

Functional residue map

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

Catalytic / active sites (1): 47–48 (reactive bond)

Disulfide bonds (3): 32–67, 45–64, 53–85

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 51 (showing top): GOBP_NEGATIVE_REGULATION_OF_PROTEOLYSIS, GOBP_INFLAMMATORY_RESPONSE, XU_GH1_AUTOCRINE_TARGETS_UP, GOBP_NEGATIVE_REGULATION_OF_MULTICELLULAR_ORGANISMAL_PROCESS, GOBP_PRODUCTION_OF_MOLECULAR_MEDIATOR_INVOLVED_IN_INFLAMMATORY_RESPONSE, GOBP_CYTOKINE_PRODUCTION, GOBP_NEGATIVE_REGULATION_OF_PROTEIN_METABOLIC_PROCESS, ACEVEDO_METHYLATED_IN_LIVER_CANCER_DN, GOBP_NEGATIVE_REGULATION_OF_CYTOKINE_PRODUCTION, GOBP_REGULATION_OF_PROTEOLYSIS, chr5q32, GOBP_PROTEOLYSIS, GOMF_PEPTIDASE_REGULATOR_ACTIVITY, GOMF_SERINE_TYPE_ENDOPEPTIDASE_INHIBITOR_ACTIVITY, GOMF_ENZYME_INHIBITOR_ACTIVITY

GO Biological Process (2): inflammatory response (GO:0006954), negative regulation of cytokine production involved in inflammatory response (GO:1900016)

GO Molecular Function (3): serine-type endopeptidase inhibitor activity (GO:0004867), protein binding (GO:0005515), peptidase inhibitor activity (GO:0030414)

GO Cellular Component (2): obsolete extracellular space (GO:0005615), extracellular region (GO:0005576)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
defense response	1
negative regulation of cytokine production	1
cytokine production involved in inflammatory response	1
regulation of cytokine production involved in inflammatory response	1
serine-type endopeptidase activity	1
endopeptidase inhibitor activity	1
binding	1
enzyme inhibitor activity	1
peptidase activity	1
peptidase regulator activity	1
cellular anatomical structure	1

Protein interactions and networks

STRING

521 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SPINK7	SPINK6	Q6UWN8	588
SPINK7	CAPN14	A8MX76	580
SPINK7	SPINK5	Q9NQ38	579
SPINK7	SPINK13	Q1W4C9	571
SPINK7	FXYD4	P59646	552
SPINK7	OR1E1	P30953	531
SPINK7	SPINK8	P0C7L1	509
SPINK7	COXFA4L2	Q9NRX3	471
SPINK7	CRISP2	P16562	470
SPINK7	PILRA	Q9UKJ1	460
SPINK7	KLK13	Q9UKR3	453
SPINK7	DSG1	Q02413	447
SPINK7	SPATA18	Q8TC71	445
SPINK7	UNC45B	Q8IWX7	438
SPINK7	SPINK9	Q5DT21	431

IntAct

28 interactions, top by confidence:

A	B	Type	Score
MT2A	SPINK7	psi-mi:“MI:0915”(physical association)	0.700
SPINK7	MT2A	psi-mi:“MI:0407”(direct interaction)	0.700
SPINK7	MT2A	psi-mi:“MI:0403”(colocalization)	0.700
SPINK7	MT2A	psi-mi:“MI:0915”(physical association)	0.700
	SPINK7	psi-mi:“MI:0915”(physical association)	0.550
SPINK7	MT1H	psi-mi:“MI:0915”(physical association)	0.550
MT1G	SPINK7	psi-mi:“MI:0915”(physical association)	0.550
SPINK7	EPB42	psi-mi:“MI:0915”(physical association)	0.550
MRPS12	SPINK7	psi-mi:“MI:0915”(physical association)	0.550
SPINK7	RABL6	psi-mi:“MI:0915”(physical association)	0.550
SPINK7	MT1G	psi-mi:“MI:0915”(physical association)	0.550
EPB42	SPINK7	psi-mi:“MI:0915”(physical association)	0.550
SPINK7	MRPS12	psi-mi:“MI:0915”(physical association)	0.550
SPINK7		psi-mi:“MI:0915”(physical association)	0.550
MT1H	SPINK7	psi-mi:“MI:0915”(physical association)	0.550
SPINK7	UBB	psi-mi:“MI:0914”(association)	0.530

BioGRID (33): LYPD1 (Affinity Capture-MS), SMPX (Affinity Capture-MS), BIRC2 (Affinity Capture-MS), ZER1 (Affinity Capture-MS), UBB (Affinity Capture-MS), IDE (Affinity Capture-MS), ARMC8 (Affinity Capture-MS), GID8 (Affinity Capture-MS), MT2A (Two-hybrid), MT1H (Two-hybrid), MT1G (Two-hybrid), EPB42 (Two-hybrid), MRPS12 (Two-hybrid), RABL6 (Two-hybrid), MT2A (Two-hybrid)

ESM2 similar proteins: A0A2P1BSU3, A1BN60, A7VN14, A7VN15, A7VN16, A7VN17, B3F211, O02826, O08540, O42146, O57340, O97935, O97936, O97949, P01001, P01215, P01220, P01225, P01226, P01228, P04155, P08118, P0C552, P0C553, P0DKR6, P0DQG7, P16035, P16368, P25142, P49122, P58062, P83242, P97580, Q28767, Q2PUH2, Q3HRV5, Q3YC03, Q53B52, Q63467, Q863T4

Diamond homologs: A2ASQ1, A5YT95, D3ZVP0, O35679, O60575, O62650, O95633, P00995, P00996, P00997, P00998, P01003, P01005, P04542, P05560, P09036, P09655, P09656, P0C7L1, P0DKM8, P0DKM9, P0DKT1, P0DKT2, P0DKT3, P0DKT4, P0DKT5, P10184, P10669, P11706, P16226, P19883, P20155, P21674, P25304, P31514, P31696, P34953, P37109, P47931, P50291

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

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

Top pathogenic / likely-pathogenic (0)

SpliceAI

365 predictions. Top by Δscore:

Variant	Effect	Δscore
5:148313400:G:GG	donor_gain	1.0000
5:148312543:AGGTA:A	donor_loss	0.9900
5:148312544:GGTA:G	donor_loss	0.9900
5:148313372:A:AG	acceptor_gain	0.9900
5:148313373:G:GG	acceptor_gain	0.9900
5:148313373:GAA:G	acceptor_gain	0.9900
5:148313395:AAAAA:A	donor_gain	0.9900
5:148313396:AAAA:A	donor_gain	0.9900
5:148313398:AA:A	donor_gain	0.9900
5:148313402:AA:A	donor_loss	0.9900
5:148313368:TTTCA:T	acceptor_loss	0.9800
5:148313370:TCA:T	acceptor_loss	0.9800
5:148313371:CAG:C	acceptor_loss	0.9800
5:148313372:AG:A	acceptor_loss	0.9800
5:148313373:GA:G	acceptor_gain	0.9800
5:148313403:AG:A	donor_loss	0.9800
5:148313404:G:GG	donor_gain	0.9800
5:148315633:CCTTA:C	acceptor_loss	0.9800
5:148315634:CTTA:C	acceptor_loss	0.9800
5:148315635:TTA:T	acceptor_loss	0.9800
5:148315636:TA:T	acceptor_loss	0.9800
5:148315638:G:GT	acceptor_loss	0.9800
5:148312545:G:GG	donor_gain	0.9700
5:148315637:A:AG	acceptor_gain	0.9700
5:148315638:G:GG	acceptor_gain	0.9700
5:148313402:AAG:A	acceptor_loss	0.9600
5:148315359:TCA:T	donor_gain	0.9500
5:148313403:A:AG	donor_gain	0.9400
5:148314225:G:GG	donor_gain	0.9400
5:148313401:TAAG:T	acceptor_loss	0.9300

AlphaMissense

552 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:148314202:T:A	C64S	0.993
5:148314203:G:C	C64S	0.993
5:148314169:T:A	C53S	0.992
5:148314170:G:C	C53S	0.992
5:148315679:T:A	C85S	0.992
5:148315680:G:C	C85S	0.992
5:148314211:T:A	C67S	0.991
5:148314212:G:C	C67S	0.991
5:148315681:C:G	C85W	0.989
5:148314198:T:A	N62K	0.987
5:148314198:T:G	N62K	0.987
5:148314145:T:A	C45S	0.986
5:148314146:G:C	C45S	0.986
5:148315679:T:C	C85R	0.985
5:148314106:T:A	C32S	0.984
5:148314107:G:C	C32S	0.984
5:148314178:G:C	D56H	0.983
5:148314202:T:C	C64R	0.982
5:148314211:T:C	C67R	0.981
5:148315680:G:A	C85Y	0.981
5:148314145:T:C	C45R	0.979
5:148314197:A:T	N62I	0.979
5:148314169:T:C	C53R	0.978
5:148314172:G:T	G54C	0.977
5:148314173:G:A	G54D	0.977
5:148314173:G:T	G54V	0.977
5:148314180:C:A	D56E	0.977
5:148314180:C:G	D56E	0.977
5:148314167:T:A	V52D	0.974
5:148314146:G:A	C45Y	0.973

dbSNP variants (sampled 300 via entrez): RS1000117636 (5:148315387 G>A), RS1001420805 (5:148313509 C>A,T), RS1001687909 (5:148312967 G>A), RS1001893583 (5:148313306 CTT>C), RS1002044665 (5:148311241 A>G), RS1002117619 (5:148312642 A>G), RS1002416768 (5:148311582 T>C), RS1002715481 (5:148314159 C>T), RS1002938235 (5:148316407 A>C,G), RS1003094122 (5:148314333 T>C), RS1003824152 (5:148311943 A>C), RS1004082747 (5:148311624 G>A), RS1006346409 (5:148313467 G>A,T), RS1006418760 (5:148313039 G>C), RS1007044243 (5:148313876 C>T)

Disease associations

OMIM: gene MIM:617288 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST006944_39	Experiencing mood swings	5.000000e-09
GCST007611_18	Chronic obstructive pulmonary disease or high blood pressure (pleiotropy)	1.000000e-13

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0008475	mood instability measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

9 total (human), top 9 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenate	decreases expression, increases abundance	1
CGP 52608	affects binding, increases reaction	1
Arsenic	decreases expression, increases abundance	1
Benzo(a)pyrene	affects methylation	1
Sodium Dodecyl Sulfate	increases expression	1
Tetrachlorodibenzodioxin	increases expression	1
Aflatoxin B1	decreases methylation	1
Cadmium Chloride	increases expression	1
Lactic Acid	decreases expression	1

Clinical trials (associated diseases)

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