SPINK1

protein-coding

serine peptidase inhibitor Kazal type 1, the group of Serine peptidase inhibitors, Kazal type

Gene summary

The protein encoded by this gene is a trypsin inhibitor, which is secreted from pancreatic acinar cells into pancreatic juice. It is thought to function in the prevention of trypsin-catalyzed premature activation of zymogens within the pancreas and the pancreatic duct. Mutations in this gene are associated with hereditary pancreatitis and tropical calcific pancreatitis. [provided by RefSeq, Oct 2008]

MANE transcript

NM_001379610.1

Inheritance

AD, AR

ClinVar variants

P:17U:93B:77

Top phenotype

Pancreatitis, hereditary; Tropical calcific pancreatitis

gnomAD constraint

pLI —, LoF o/e 0.24

Max pathogenic AF

—

Genomic locus

chr5:147,824,572-147,831,671

External References & Databases

Ensembl (ENSG00000164266)

Transcript & Mutation Effects

hg38 • Region Span ~7.1 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

hereditary chronic pancreatitisMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0008185

Submitter: PanelApp Australia

hereditary chronic pancreatitisNO_KNOWN

Inheritance Pattern: Unknown

Disease ID:MONDO:0008185

Submitter: Labcorp Genetics (formerly Invitae)

hereditary chronic pancreatitisSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0008185

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Pancreatitis, hereditary; Tropical calcific pancreatitisAD/AR

Manifestation: Endocrine; Gastrointestinal; Oncologic

Intervention: Gastrointestinal; Endocrine; Oncologic

Rationale: Dietary measures (eg, low-fat diet with frequent feeding), hydration, and antioxidants, with avoidance of precipitants such as alcohol and tobacco, can beneficial in order to ameliorate episodes of pancreatitis; Individuals may be at increased risk of insulin-dependent, ketosis-resistant diabetes mellitus, and awareness may enable early diagnosis and management; Individuals may be at high risk of pancreatic cancer, and awareness may allow early diagnosis and treatment

Refs: 2813331; 10691414; 10835640; 11938439; 12011155; 16492714; 17274009; 18184119; 18755888; 20543535; 20664488; 21610753; 20676769; 21415673; 21375584; 20977904; 22228370; 24624459

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SPINK1 variants in ClinVar

10 Conditions Cataloged

Hereditary pancreatitisTotal: 202

not providedTotal: 39

not specifiedTotal: 36

Tropical pancreatitisTotal: 12

SPINK1-related disorderTotal: 8

Pancreatitis, chronic, susceptibility toTotal: 2

Diabetes mellitusTotal: 1

Chronic pancreatitisTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001379610.1. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous				56 clinvar	2 clinvar	58
missense	1 clinvar	1 clinvar	84 clinvar	18 clinvar	1 clinvar	105
nonsense	2 clinvar	1 clinvar	1 clinvar			4
start loss	2 clinvar	1 clinvar	1 clinvar			4
frameshift	1 clinvar	3 clinvar				4
splice donor/acceptor (+/-2bp)	2 clinvar	3 clinvar	7 clinvar			12
Total	8	9	93	74	3	187

Highest pathogenic variant AF is 0.00011372789

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 9 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001379610.1	RefSeq	NP_001366539.1	4	MANE Select
ENST00000296695.10	Ensembl	ENSP00000296695.5	4	MANE Select
NM_001354966.2	RefSeq	NP_001341895.1	4	Standard
NM_003122.5	RefSeq	NP_003113.2	4	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Androgen Receptor Network in Prostate Cancer

Biological Process

negative regulation of nitric oxide mediated signal transduction
sperm capacitation
negative regulation of peptidyl-tyrosine phosphorylation
regulation of acrosome reaction
negative regulation of calcium ion import

Molecular Function

endopeptidase inhibitor activity
serine-type endopeptidase inhibitor activity
protein binding

Cellular Component

extracellular exosome

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000296695
Coding exons: 4
Length: 7219
Individuals with no LoFs: 125456
Homozygous LoFs: 0
Heterozygous LoFs: 82
Defined: 125538
p: 0.000327

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.123	45	42.7	1.05	0.00000216	501
Missense (PolyPhen)		13	14.521	0.89527		164
Synonymous	-0.773	18	14.3	1.26	6.11e-7	146
Loss of Function	1.43	1	4.14	0.241	1.73e-7	54

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000087	0.000087	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.0033	0.0033	notable
Finnish	0	0.0	absent
European (Non-Finnish)	0.00012	0.00012	rare
South Asian	0.000066	0.000065	rare
Other	0.00033	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Serine protease inhibitor which exhibits anti-trypsin activity (PubMed:7142173). In the pancreas, protects against trypsin-catalyzed premature activation of zymogens (By similarity). {ECO:0000250|UniProtKB:P09036, ECO:0000269|PubMed:7142173}.;
Disease: DISEASE: Pancreatitis, hereditary (PCTT) [MIM:167800]: A disease characterized by pancreas inflammation, permanent destruction of the pancreatic parenchyma, maldigestion, and severe abdominal pain attacks. {ECO:0000269|PubMed:10691414, ECO:0000269|PubMed:10835640, ECO:0000269|PubMed:12974284, ECO:0000269|PubMed:18617776, ECO:0000269|PubMed:19888199}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.; DISEASE: Tropical calcific pancreatitis (TCP) [MIM:608189]: Idiopathic, juvenile, nonalcoholic form of chronic pancreatitis widely prevalent in several tropical countries. It can be associated with fibrocalculous pancreatic diabetes (FCPD) depending on both environmental and genetic factors. TCP differs from alcoholic pancreatitis by a much younger age of onset, pancreatic calcification, a high incidence of insulin dependent but ketosis resistant diabetes mellitus, and an exceptionally high incidence of pancreatic cancer. {ECO:0000269|PubMed:12011155, ECO:0000269|PubMed:12187509}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.179

Intolerance Scores

LoFtool: 0.542
RVIS EVS: 0.81
RVIS percentile EVS: 87.82

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.547

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium