CST1

protein-coding

cystatin SN, the group of Cystatins, type 2

Gene summary

The cystatin superfamily encompasses proteins that contain multiple cystatin-like sequences. Some of the members are active cysteine protease inhibitors, while others have lost or perhaps never acquired this inhibitory activity. There are three inhibitory families in the superfamily, including the type 1 cystatins (stefins), type 2 cystatins and the kininogens. The type 2 cystatin proteins are a class of cysteine proteinase inhibitors found in a variety of human fluids and secretions, where they appear to provide protective functions. The cystatin locus on chromosome 20 contains the majority of the type 2 cystatin genes and pseudogenes. This gene is located in the cystatin locus and encodes a cysteine proteinase inhibitor found in saliva, tears, urine, and seminal fluid. [provided by RefSeq, Jul 2008]

MANE transcript

NM_001898.3

Inheritance

ClinVar variants

U:39B:7

Top phenotype

—

gnomAD constraint

pLI —, LoF o/e 1.88

Max pathogenic AF

—

Genomic locus

chr20:23,747,562-23,751,268

External References & Databases

Ensembl (ENSG00000170373)

Transcript & Mutation Effects

hg38 • Region Span ~3.7 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

male infertility with azoospermia or oligozoospermia due to single gene mutationLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0018393

Submitter: King Faisal Specialist Hospital and Research Center

Alhathal et al., 2020 (PMID: 32719396) reported a LOF variant in a large male infertility cohort (n=285 infertile man and case–control fertile man) and also the gene is scored according to ClinGen classification. Limited with total score of 3. Single-variant analysis (3 points).

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CST1 variants in ClinVar

2 Conditions Cataloged

not specifiedTotal: 42

not providedTotal: 4

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001898.3. 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				2 clinvar		2
missense			37 clinvar	5 clinvar		42
nonsense						0
start loss						0
frameshift			2 clinvar			2
splice donor/acceptor (+/-2bp)						0
Total	0	0	39	7	0	46

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 6 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001898.3	RefSeq	NP_001889.2	3	MANE Select
ENST00000304749.7	Ensembl	ENSP00000305731.2	3	MANE Select
ENST00000398402.1	Ensembl	ENSP00000381439.1	3	Standard
ENST00000398402.2	Ensembl	ENSP00000381439.1	3	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Salivary secretion - Homo sapiens (human)
Vitamin D Receptor Pathway

Biological Process

detection of chemical stimulus involved in sensory perception of bitter taste
negative regulation of endopeptidase activity

Molecular Function

cysteine-type endopeptidase inhibitor activity
protein binding

Cellular Component

extracellular space

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000304749
Coding exons: 3
Length: 3716
Individuals with no LoFs: 125715
Homozygous LoFs: 0
Heterozygous LoFs: 30
Defined: 125745
p: 0.000119

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-2.20	141	84.1	1.68	0.00000508	910
Missense (PolyPhen)		49	30.876	1.587		389
Synonymous	-3.52	63	36.1	1.75	0.00000233	273
Loss of Function	-1.79	9	4.78	1.88	2.02e-7	56

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00043	0.00043	rare
Latino/Admixed American	0.000087	0.000087	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00027	0.00027	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000079	0.000079	rare
South Asian	0.00013	0.00013	rare
Other	0.00033	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Human saliva appears to contain several cysteine proteinase inhibitors that are immunologically related to cystatin S but that differ in their specificity due to amino acid sequence differences. Cystatin SN, with a pI of 7.5, is a much better inhibitor of papain and dipeptidyl peptidase I than is cystatin S, although both inhibit ficin equally well.;

Recessive Scores

pRec: 0.112

Intolerance Scores

LoFtool: 0.870
RVIS EVS: 0.42
RVIS percentile EVS: 76.96

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.0778

Gene Damage Prediction

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