NCSTN

protein-coding

nicastrin

Gene summary

This gene encodes a type I transmembrane glycoprotein that is an integral component of the multimeric gamma-secretase complex. The encoded protein cleaves integral membrane proteins, including Notch receptors and beta-amyloid precursor protein, and may be a stabilizing cofactor required for gamma-secretase complex assembly. The cleavage of beta-amyloid precursor protein yields amyloid beta peptide, the main component of the neuritic plaque and the hallmark lesion in the brains of patients with Alzheimer's disease; however, the nature of the encoded protein's role in Alzheimer's disease is not known for certain. Mutations in this gene are associated with familial acne inversa. A pseudogene of this gene is present on chromosome 21. Alternatively spliced transcript variants of this gene have been described, but the full-length nature of some of these variants has not been determined. [provided by RefSeq, Feb 2014]

MANE transcript

NM_015331.3

Inheritance

ClinVar variants

P:26U:278B:128

Top phenotype

Acne inversa, familial 1

gnomAD constraint

pLI —, LoF o/e 0.1

Max pathogenic AF

—

Genomic locus

chr1:160,343,294-160,358,952

External References & Databases

Ensembl (ENSG00000162736)

Transcript & Mutation Effects

hg38 • Region Span ~15.7 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

acne inversa, familial, 1MODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0007728

Submitter: Ambry Genetics

acne inversa, familial, 1STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007728

Submitter: Genomics England PanelApp

acne inversa, familial, 1STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007728

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Acne inversa, familial 1AD

Manifestation: Dermatologic

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: 20929727; 22622421

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to NCSTN variants in ClinVar

6 Conditions Cataloged

not providedTotal: 498

Inborn genetic diseasesTotal: 88

not specifiedTotal: 43

Acne inversa, familial, 1Total: 23

NCSTN-related disorderTotal: 15

Abnormality of the skinTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_015331.3. 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			9 clinvar	110 clinvar	9 clinvar	128
missense	1 clinvar	1 clinvar	259 clinvar	7 clinvar	2 clinvar	270
nonsense	7 clinvar	2 clinvar	1 clinvar			10
start loss						0
frameshift	4 clinvar	5 clinvar	2 clinvar			11
splice donor/acceptor (+/-2bp)	2 clinvar	4 clinvar	7 clinvar			13
Total	14	12	278	117	11	432

Highest pathogenic variant AF is 0.0000034238087

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 70 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_015331.3	RefSeq	NP_056146.1	17	MANE Select
ENST00000294785.10	Ensembl	ENSP00000294785.5	17	MANE Select
NM_001290184.2	RefSeq	NP_001277113.1	17	Standard
NM_001290186.2	RefSeq	NP_001277115.1	14	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
ncstn	Danio rerio	Structure: pigment cell Quality: quality abnormal

Gene / Model

Organism

Observed Phenotype

ncstn

Danio rerio

Structure: pigment cell

Quality: quality

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Alzheimer,s disease - Homo sapiens (human)
Notch signaling pathway - Homo sapiens (human)
NOTCH-Core
Alzheimers Disease
Notch Signaling Pathway

Biological Process

myeloid cell homeostasis
proteolysis
membrane protein ectodomain proteolysis
Notch receptor processing
protein processing

Molecular Function

endopeptidase activity
protein binding

Cellular Component

mitochondrion
lysosomal membrane
endoplasmic reticulum
Golgi apparatus
plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000294785
Coding exons: 17
Length: 15681
Individuals with no LoFs: 125740
Homozygous LoFs: 0
Heterozygous LoFs: 8
Defined: 125748
p: 0.0000318

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.43	302	381	0.794	0.0000225	4615
Missense (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

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00012	0.00012	rare
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000054	0.000054	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.000027	0.000026	rare
South Asian	0.000033	0.000033	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

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.;

Recessive Scores

pRec: 0.356

Intolerance Scores

LoFtool: 0.159
RVIS EVS: -0.58
RVIS percentile EVS: 18.72

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.975

Gene Damage Prediction

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