NCSTN

nicastrin

Basic information

Region (hg38): 1:160343293-160358952

Links

ENSG00000162736 ∙ NCBI:23385 ∙ OMIM:605254 ∙ HGNC:17091 ∙ Uniprot:Q92542 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• acne inversa, familial, 1 (Strong), mode of inheritance: AD
• acne inversa, familial, 1 (Moderate), mode of inheritance: AD
• acne inversa, familial, 1 (Strong), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Acne inversa, familial 1	AD	General	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	Dermatologic	20929727; 22622421

ClinVar

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

• not provided (295 variants)
• Inborn genetic diseases (19 variants)
• Acne inversa, familial, 1 (9 variants)
• not specified (1 variants)
• NCSTN-related condition (1 variants)
• Abnormality of the skin (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the NCSTN 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			4	53	17	74
missense			134	3	3	140
nonsense	4					4
start loss						0
frameshift	2	1				3
inframe indel			2			2
splice donor/acceptor (+/-2bp)		2			2	4
splice region	1		11	15	3	30
non coding			4	44	5	53
Total	6	3	144	100	27

Variants in NCSTN

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

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

Position	Type	Phenotype	Significance	ClinVar
1-160343391-G-C		NCSTN-related disorder	Likely benign (Sep 06, 2019)
1-160343408-AG-A			Pathogenic (Feb 02, 2018)
1-160343410-G-A			Uncertain significance (Dec 12, 2023)
1-160343410-G-T			Uncertain significance (Dec 30, 2023)
1-160343411-G-T			Benign (Dec 02, 2023)
1-160343417-C-G			Uncertain significance (Sep 22, 2022)
1-160343417-C-T			Likely benign (Jan 01, 2024)
1-160343419-C-T			Uncertain significance (May 22, 2023)
1-160343422-G-A			Uncertain significance (Dec 18, 2021)
1-160343422-G-C			Uncertain significance (Jul 29, 2023)
1-160343436-A-G			Uncertain significance (Nov 10, 2022)
1-160343441-G-C			Likely benign (Jan 04, 2024)
1-160343444-T-G			Likely benign (Jun 13, 2022)
1-160343445-C-G			Uncertain significance (Jan 29, 2024)
1-160343448-C-G			Uncertain significance (Aug 27, 2023)
1-160343450-T-C		NCSTN-related disorder	Benign/Likely benign (Mar 22, 2023)
1-160343451-C-T			Uncertain significance (Nov 13, 2023)
1-160343452-G-A			Uncertain significance (Oct 16, 2022)
1-160343457-C-T			Likely benign (Nov 10, 2022)
1-160343458-T-C			Uncertain significance (Jul 03, 2022)
1-160343469-G-A			Uncertain significance (Dec 17, 2022)
1-160343471-C-T			Likely benign (Nov 22, 2022)
1-160343475-C-T		NCSTN-related disorder	Likely benign (Nov 28, 2023)
1-160343478-G-A			Uncertain significance (Mar 24, 2023)
1-160343486-G-GGCCT			Likely benign (Aug 13, 2022)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
NCSTN	protein_coding	protein_coding	ENST00000294785	17	15681

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.999	0.000579	125740	0	8	125748	0.0000318

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.43	302	381	0.794	0.0000225	4615
Missense in Polyphen		53	102.54	0.51685		1251
Synonymous	-0.182	147	144	1.02	0.00000828	1425
Loss of Function	5.20	4	39.1	0.102	0.00000233	426

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000123	0.000123
Ashkenazi Jewish	0.00	0.00
East Asian	0.0000544	0.0000544
Finnish	0.0000462	0.0000462
European (Non-Finnish)	0.0000266	0.0000264
Middle Eastern	0.0000544	0.0000544
South Asian	0.0000327	0.0000327
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Essential subunit of the gamma-secretase complex, an endoprotease complex that catalyzes the intramembrane cleavage of integral membrane proteins such as Notch receptors and APP (amyloid-beta precursor protein) (PubMed:10993067, PubMed:12679784, PubMed:25043039, PubMed:26280335). The gamma- secretase complex plays a role in Notch and Wnt signaling cascades and regulation of downstream processes via its role in processing key regulatory proteins, and by regulating cytosolic CTNNB1 levels. {ECO:0000269|PubMed:10993067, ECO:0000269|PubMed:12679784, ECO:0000269|PubMed:25043039, ECO:0000269|PubMed:26280335}.
• Disease: DISEASE: Acne inversa, familial, 1 (ACNINV1) [MIM:142690]: A chronic relapsing inflammatory disease of the hair follicles characterized by recurrent draining sinuses, painful skin abscesses, and disfiguring scars. Manifestations typically appear after puberty. {ECO:0000269|PubMed:20929727, ECO:0000269|PubMed:21430701, ECO:0000269|PubMed:21495993}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Alzheimer,s disease - Homo sapiens (human);Notch signaling pathway - Homo sapiens (human);NOTCH-Core;Alzheimers Disease;Notch Signaling Pathway;Notch Signaling Pathway;Notch Signaling Pathway;Notch;Neutrophil degranulation;Disease;Signal Transduction;Extracellular matrix organization;DroToll-like;Notch;Innate Immune System;Immune System;Signaling by NOTCH1;Signaling by NOTCH2;NOTCH3 Activation and Transmission of Signal to the Nucleus;Signaling by NOTCH3;Signaling by NOTCH4;Signaling by NOTCH;A third proteolytic cleavage releases NICD;NRIF signals cell death from the nucleus;NOTCH2 Activation and Transmission of Signal to the Nucleus;Degradation of the extracellular matrix;Death Receptor Signalling;Regulated proteolysis of p75NTR;p75 NTR receptor-mediated signalling;Notch signaling pathway;Nuclear signaling by ERBB4;Signaling by ERBB4;Constitutive Signaling by NOTCH1 PEST Domain Mutants;Signaling by NOTCH1 PEST Domain Mutants in Cancer;Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants;Signaling by NOTCH1 HD+PEST Domain Mutants in Cancer;Signaling by NOTCH1 in Cancer;Signaling by Receptor Tyrosine Kinases;Diseases of signal transduction;p75(NTR)-mediated signaling;Cell death signalling via NRAGE, NRIF and NADE;Presenilin action in Notch and Wnt signaling;Syndecan-3-mediated signaling events;Activated NOTCH1 Transmits Signal to the Nucleus (Consensus)

Recessive Scores

• pRec: 0.356

Intolerance Scores

• loftool: 0.159
• rvis_EVS: -0.58
• rvis_percentile_EVS: 18.72

Haploinsufficiency Scores

• pHI: 0.562
• hipred: Y
• hipred_score: 0.630
• ghis: 0.545

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: S
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.975

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Ncstn
• Phenotype: embryo phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); normal 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; cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); neoplasm; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); vision/eye phenotype; immune system phenotype; renal/urinary system 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); growth/size/body region phenotype; craniofacial phenotype; cellular phenotype

Zebrafish Information Network

• Gene name: ncstn
• Affected structure: pigment cell
• Phenotype tag: abnormal
• Phenotype quality: quality

Gene ontology

• Biological process: myeloid cell homeostasis;proteolysis;membrane protein ectodomain proteolysis;Notch receptor processing;protein processing;amyloid-beta formation;Notch receptor processing, ligand-dependent;T cell proliferation;amyloid precursor protein metabolic process;amyloid precursor protein catabolic process;positive regulation of catalytic activity;neutrophil degranulation;epithelial cell proliferation
• Cellular component: mitochondrion;lysosomal membrane;endoplasmic reticulum;Golgi apparatus;plasma membrane;integral component of plasma membrane;focal adhesion;endosome membrane;membrane;integral component of membrane;azurophil granule membrane;melanosome;extracellular exosome;gamma-secretase complex;integral component of presynaptic membrane
• Molecular function: endopeptidase activity;protein binding