SPINK2

protein-coding

serine peptidase inhibitor Kazal type 2, the group of Serine peptidase inhibitors, Kazal type

Gene summary

This gene encodes a member of the family of serine protease inhibitors of the Kazal type (SPINK). The encoded protein acts as a trypsin and acrosin inhibitor in the genital tract and is localized in the spermatozoa. The protein has been associated with the progression of lymphomas. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2012]

MANE transcript

NM_001271718.2

Inheritance

ClinVar variants

U:14B:2

Top phenotype

Spermatogenic failure 29

gnomAD constraint

pLI —, LoF o/e 0.5

Max pathogenic AF

—

Genomic locus

chr4:56,809,860-56,821,742

External References & Databases

Ensembl (ENSG00000128040)

Transcript & Mutation Effects

hg38 • Region Span ~11.9 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

spermatogenic failure 29STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0054733

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Spermatogenic failure 29AR

Manifestation: Genitourinary

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 28554943

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SPINK2 variants in ClinVar

3 Conditions Cataloged

not specifiedTotal: 15

SPINK2-related disorderTotal: 2

Spermatogenic failure 29Total: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001271718.2. 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	1 clinvar	2
missense			14 clinvar			14
nonsense						0
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)						0
Total	0	0	14	1	1	16

Highest pathogenic variant AF is 0.0000024891535

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 23 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001271718.2	RefSeq	NP_001258647.1	4	MANE Select
ENST00000506738.6	Ensembl	ENSP00000425961.1	4	MANE Select
NM_001271719.2	RefSeq	NP_001258648.1	3	Standard
NM_001271720.2	RefSeq	NP_001258649.1	4	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

acrosome assembly
spermatogenesis
spermatid development
negative regulation of serine-type endopeptidase activity

Molecular Function

endopeptidase inhibitor activity
serine-type endopeptidase inhibitor activity
protein binding

Cellular Component

acrosomal vesicle
extracellular region

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000248701
Coding exons: 4
Length: 11883
Individuals with no LoFs: 119233
Homozygous LoFs: 0
Heterozygous LoFs: 1
Defined: 119234
p: 0.00000419

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.663	30	42.1	0.712	0.00000196	524
Missense (PolyPhen)		7	13.73	0.50985		175
Synonymous	0.357	14	15.8	0.886	6.88e-7	165
Loss of Function	0.931	2	4.01	0.498	1.68e-7	54

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.0000095	0.0000095	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Strong inhibitor of acrosin in male and/or female genital tract. Also inhibits trypsin. {ECO:0000269|PubMed:19422058}.;

Intolerance Scores

RVIS EVS: 0.01
RVIS percentile EVS: 54.63

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.114

Gene Damage Prediction

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