SPINT2

protein-coding

serine peptidase inhibitor, Kunitz type 2

Gene summary

This gene encodes a transmembrane protein with two extracellular Kunitz domains that inhibits a variety of serine proteases. The protein inhibits HGF activator which prevents the formation of active hepatocyte growth factor. This gene is a putative tumor suppressor, and mutations in this gene result in congenital sodium diarrhea. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2009]

MANE transcript

NM_021102.4

Inheritance

AR, AD

ClinVar variants

P:18U:67B:61

Top phenotype

Diarrhea 3, secretory sodium, congenital, with or without other congenital anomalies

gnomAD constraint

pLI —, LoF o/e 0.52

Max pathogenic AF

—

Genomic locus

chr19:38,244,035-38,292,615

External References & Databases

Ensembl (ENSG00000167642)

Transcript & Mutation Effects

hg38 • Region Span ~48.6 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

congenital secretory sodium diarrhea 3STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0010036

Submitter: PanelApp Australia

congenital secretory sodium diarrhea 3STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0010036

Submitter: Labcorp Genetics (formerly Invitae)

syndromic congenital sodium diarrheaDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0034204

Submitter: G2P

congenital secretory sodium diarrhea 3MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0010036

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Diarrhea 3, secretory sodium, congenital, with or without other congenital anomaliesAD

Manifestation: Craniofacial; Dermatologic; Gastrointestinal; Hematologic; Musculoskeletal; Ophthalmologic

Intervention: Gastrointestinal

Rationale: Due to fecal sodium loss, individuals may present with severe (potentially lethal) secretory diarrhea and related electrolyte/metabolic derangements, including hyponatremic metabolic acidosis, and recognition may allow appropriate medical management, which includes parenteral nutrition (weaning from parenteral nutrition, with oral sodium citrate supplementation, is possible in childhood

Refs: 11113072; 17786112; 19185281; 20009592

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SPINT2 variants in ClinVar

6 Conditions Cataloged

not providedTotal: 167

Inborn genetic diseasesTotal: 29

Congenital secretory sodium diarrhea 3Total: 15

not specifiedTotal: 14

SPINT2-related disorderTotal: 10

Congenital sodium diarrheaTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_021102.4. 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			1 clinvar	54 clinvar		55
missense	2 clinvar	3 clinvar	55 clinvar	5 clinvar	2 clinvar	67
nonsense	1 clinvar	1 clinvar				2
start loss	3 clinvar					3
frameshift	1 clinvar	1 clinvar	1 clinvar			3
splice donor/acceptor (+/-2bp)	3 clinvar	3 clinvar	10 clinvar			16
Total	10	8	67	59	2	146

Highest pathogenic variant AF is 0.00019660403

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 44 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_021102.4	RefSeq	NP_066925.1	7	MANE Select
ENST00000301244.12	Ensembl	ENSP00000301244.5	7	MANE Select
NM_001166103.2	RefSeq	NP_001159575.1	6	Standard
ENST00000454580.7	Ensembl	ENSP00000389788.2	6	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Signal Transduction
MET Receptor Activation
Signaling by MET
Signaling by MST1
Signaling by Receptor Tyrosine Kinases

Biological Process

neural tube closure
establishment or maintenance of cell polarity
negative regulation of endopeptidase activity
negative regulation of cell-cell adhesion
epithelial cell morphogenesis involved in placental branching

Molecular Function

endopeptidase inhibitor activity
serine-type endopeptidase inhibitor activity

Cellular Component

extracellular region
cytoplasm
plasma membrane
integral component of membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000301244
Coding exons: 7
Length: 48580
Individuals with no LoFs: 125726
Homozygous LoFs: 0
Heterozygous LoFs: 22
Defined: 125748
p: 0.0000875

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.997	118	153	0.773	0.00000960	1631
Missense (PolyPhen)		25	36.717	0.68088		436
Synonymous	0.477	60	64.9	0.925	0.00000400	517
Loss of Function	1.61	7	13.4	0.523	6.84e-7	145

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
Latino/Admixed American	0.000029	0.000029	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00011	0.00011	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.00015	0.00015	rare
South Asian	0.000033	0.000033	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Inhibitor of HGF activator. Also inhibits plasmin, plasma and tissue kallikrein, and factor XIa.;
Disease: DISEASE: Diarrhea 3, secretory sodium, congenital, with or without other congenital anomalies (DIAR3) [MIM:270420]: A disease characterized by life-threatening secretory diarrhea, severe metabolic acidosis and hyponatremia. Hyponatremia is secondary to extraordinarily high fecal sodium loss, with low or normal excretion of urinary sodium, in the absence of infectious, autoimmune and endocrine causes. {ECO:0000269|PubMed:19185281}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.335

Intolerance Scores

LoFtool: 0.664
RVIS EVS: 0.44
RVIS percentile EVS: 77.7

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.539

Gene Damage Prediction

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