SPINK5

serine peptidase inhibitor Kazal type 5, the group of Serine peptidase inhibitors, Kazal type

Basic information

Region (hg38): 5:148025683-148137382

Links

ENSG00000133710 ∙ NCBI:11005 ∙ OMIM:605010 ∙ HGNC:15464 ∙ Uniprot:Q9NQ38 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• Netherton syndrome (Strong), mode of inheritance: AR
• Netherton syndrome (Strong), mode of inheritance: AR
• Netherton syndrome (Supportive), mode of inheritance: AR
• Netherton syndrome (Strong), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Netherton syndrome	AR	Allergy/Immunology/Infectious; Dermatologic	The condition may not always be readily recognizable; Recurrent bacterial infections are common, and prophylactic measures, as well as prompt and aggressive treatment of infections may be beneficial; Hypernatremic dehydration in the neonatal period can result in severe sequelae, and awareness may allow preventive measures and prompt medical management	Allergy/Immunology/Infectious; Dermatologic	13582191; 7822652; 10835624; 11841556; 11693786; 17608759; 19683336; 20107740; 21573681; 21564178; 21692842; 22377713; 22837558; 23331056

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the SPINK5 gene.

• Ichthyosis linearis circumflexa (52 variants)
• not provided (29 variants)
• Netherton syndrome (16 variants)
• Susceptibility to nonsyndromic otitis media (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the SPINK5 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous		1	3	107	16	127
missense		1	323	9	16	349
nonsense	27		1			28
start loss			1			1
frameshift	32	2	1			35
inframe indel	1		10		1	12
splice donor/acceptor (+/-2bp)	9	12		1	1	23
splice region	1	3	31	40	2	77
non coding		1	11	137	176	325
Total	69	17	350	254	210

Highest pathogenic variant AF is 0.000103

Variants in SPINK5

This is a list of pathogenic ClinVar variants found in the SPINK5 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
5-148063797-G-A		Ichthyosis linearis circumflexa	Benign (Dec 11, 2023)
5-148063880-G-A			Likely benign (Oct 17, 2018)
5-148063984-A-C		Netherton syndrome	Benign (Jan 13, 2018)
5-148064026-G-A		Netherton syndrome	Benign (Apr 27, 2017)
5-148064035-C-T		Netherton syndrome	Uncertain significance (Jan 12, 2018)
5-148064046-T-A		Ichthyosis linearis circumflexa	Uncertain significance (May 22, 2022)
5-148064048-A-C		Netherton syndrome	Uncertain significance (Aug 28, 2021)
5-148064057-A-C			Uncertain significance (Jan 19, 2024)
5-148064063-T-C		Ichthyosis linearis circumflexa	Uncertain significance (Dec 02, 2022)
5-148064065-A-T		Ichthyosis linearis circumflexa	Likely benign (Mar 21, 2023)
5-148064068-G-A			Likely benign (Dec 01, 2020)
5-148064081-G-T		Ichthyosis linearis circumflexa	Uncertain significance (Jun 03, 2022)
5-148064089-C-A		Ichthyosis linearis circumflexa	Pathogenic (Mar 12, 2022)
5-148064090-C-T		Netherton syndrome • Inborn genetic diseases	Uncertain significance (Jul 12, 2022)
5-148064092-C-T		Ichthyosis linearis circumflexa	Benign (Jan 04, 2024)
5-148064107-A-G		Ichthyosis linearis circumflexa	Likely benign (May 22, 2022)
5-148064111-G-A		Ichthyosis linearis circumflexa	Likely benign (Jul 24, 2023)
5-148064115-G-A		Ichthyosis linearis circumflexa	Likely benign (Sep 22, 2022)
5-148065208-T-C			Likely benign (May 25, 2021)
5-148065222-A-G			Benign (Mar 03, 2015)
5-148065327-T-C		Ichthyosis linearis circumflexa	Likely benign (Dec 02, 2023)
5-148065344-C-A		Ichthyosis linearis circumflexa	Uncertain significance (Oct 26, 2022)
5-148065347-A-C		Netherton syndrome	Uncertain significance (Jun 20, 2022)
5-148065350-C-T		Netherton syndrome	Uncertain significance (Aug 09, 2022)
5-148065355-A-G		Ichthyosis linearis circumflexa	Uncertain significance (Jun 13, 2022)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
SPINK5	protein_coding	protein_coding	ENST00000359874	34	111607

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
4.85e-28	0.181	124681	1	125	124807	0.000505

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.278	562	581	0.967	0.0000310	7326
Missense in Polyphen		201	208.61	0.96353		2674
Synonymous	-0.326	185	179	1.03	0.00000908	1825
Loss of Function	2.04	53	71.7	0.740	0.00000410	896

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000959	0.000958
Ashkenazi Jewish	0.000199	0.000199
East Asian	0.00156	0.00156
Finnish	0.000279	0.000278
European (Non-Finnish)	0.000462	0.000459
Middle Eastern	0.00156	0.00156
South Asian	0.000365	0.000360
Other	0.000999	0.000824

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Serine protease inhibitor, probably important for the anti-inflammatory and/or antimicrobial protection of mucous epithelia. Contribute to the integrity and protective barrier function of the skin by regulating the activity of defense- activating and desquamation-involved proteases. Inhibits KLK5, it's major target, in a pH-dependent manner. Inhibits KLK7, KLK14 CASP14, and trypsin. {ECO:0000269|PubMed:10419450, ECO:0000269|PubMed:17596512, ECO:0000269|PubMed:20533828}.
• Disease: DISEASE: Netherton syndrome (NETH) [MIM:256500]: An autosomal recessive congenital ichthyosis associated with hair shaft abnormalities and anomalies of the immune system. Typical features are ichthyosis linearis circumflexa, ichthyosiform erythroderma, trichorrhexis invaginata (bamboo hair), atopic dermatitis, and hayfever. High postnatal mortality is due to failure to thrive, infections and hypernatremic dehydration. {ECO:0000269|PubMed:10835624}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Keratinization;Developmental Biology;Formation of the cornified envelope (Consensus)

Recessive Scores

• pRec: 0.293

Intolerance Scores

• loftool: 0.997
• rvis_EVS: 2.83
• rvis_percentile_EVS: 99.09

Haploinsufficiency Scores

• pHI: 0.253
• hipred: N
• hipred_score: 0.313

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: N
• gene_indispensability_score: 0.0356

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	High	High	High
Primary Immunodeficiency	High	High	High
Cancer	High	High	High

Mouse Genome Informatics

• Gene name: Spink5
• Phenotype: immune system phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); hematopoietic system phenotype; homeostasis/metabolism phenotype; integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan)

Gene ontology

• Biological process: negative regulation of antibacterial peptide production;epidermal cell differentiation;negative regulation of angiogenesis;regulation of cell adhesion;extracellular matrix organization;epithelial cell differentiation;hair cell differentiation;regulation of T cell differentiation;negative regulation of immune response;regulation of timing of anagen;cornification;negative regulation of serine-type endopeptidase activity
• Cellular component: extracellular region;cytoplasm;endoplasmic reticulum;endoplasmic reticulum membrane;cytosol;cell cortex;intracellular membrane-bounded organelle;perinuclear region of cytoplasm;epidermal lamellar body
• Molecular function: serine-type endopeptidase inhibitor activity