GeneBe

PSENEN

protein-coding

presenilin enhancer, gamma-secretase subunit

Gene summary

Presenilins, which are components of the gamma-secretase protein complex, are required for intramembranous processing of some type I transmembrane proteins, such as the Notch proteins and the beta-amyloid precursor protein. Signaling by Notch receptors mediates a wide range of developmental cell fates. Processing of the beta-amyloid precursor protein generates neurotoxic amyloid beta peptides, the major component of senile plaques associated with Alzheimer's disease. This gene encodes a protein that is required for Notch pathway signaling, and for the activity and accumulation of gamma-secretase. Mutations resulting in haploinsufficiency for this gene cause familial acne inversa-2 (ACNINV2). Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2013]

MANE transcript

NM_172341.4

Inheritance

AD

ClinVar variants

P:7U:29B:12

Top phenotype

Acne inversa, familial, 2, with or without Dowling-Degos disease

gnomAD constraint

pLI —, LoF o/e 0

Max pathogenic AF

—

Genomic locus

chr19:35,745,600-35,747,519

External References & Databases

Ensembl (ENSG00000205155)NCBI Gene (55851)OMIM (607632)HGNC:30100GenCCUniProt (Q9NZ42)AlphaFoldClinVar (PSENEN)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~1.9 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

acne inversa, familial, 2STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0013397

Submitter: PanelApp Australia

acne inversa, familial, 2STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0013397

Submitter: Labcorp Genetics (formerly Invitae)

acne inversa, familial, 2STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0013397

Submitter: Genomics England PanelApp

Dowling-Degos diseaseSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0008371

Submitter: Orphanet

acne inversa, familial, 2STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0013397

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Acne inversa, familial, 2, with or without Dowling-Degos diseaseAD

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; 28287404; 28601418Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PSENEN variants in ClinVar

3 Conditions Cataloged
not providedTotal: 52
not specifiedTotal: 15
Acne inversa, familial, 2Total: 9

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_172341.4. 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.

EffectPLPVUSLBBSum
synonymous
10
clinvar
1
clinvar
 11
missense
1
clinvar
26
clinvar
1
clinvar
 28
nonsense
1
clinvar
1
clinvar
 2
start loss
0
frameshift
1
clinvar
1
clinvar
 2
splice donor/acceptor (+/-2bp)
4
clinvar
1
clinvar
 5
Total702911148

Highest pathogenic variant AF is 0.0000027418782

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 24 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_172341.4RefSeqNP_758844.13MANE Select
ENST00000587708.7EnsemblENSP00000468411.13MANE Select
NM_001281532.3RefSeqNP_001268461.13Standard
ENST00000222266.2EnsemblENSP00000222266.13Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
psenenDanio rerio

Structure: primary motor neuron

Quality: irregular spatial pattern

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

  • membrane protein ectodomain proteolysis
  • Notch receptor processing
  • protein processing
  • amyloid-beta formation
  • Notch receptor processing, ligand-dependent

Molecular Function

  • protein binding

Cellular Component

  • endoplasmic reticulum
  • endoplasmic reticulum membrane
  • Golgi apparatus
  • plasma membrane
  • integral component of plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000587708
Coding exons
3
Length
1897
Individuals with no LoFs
0
Homozygous LoFs
0
Heterozygous LoFs
0
Defined
0
p
0.00
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense0.6444154.40.7540.00000298646
Missense (PolyPhen)1120.9830.52423258
Synonymous1.131420.50.6829.10e-7201
Loss of Function2.4206.810.003.80e-761

Population LoF Frequency

PopulationCAFp-valueStatus
African00.0absent
Latino/Admixed American00.0absent
Ashkenazi Jewish00.0absent
East Asian00.0absent
Finnish00.0absent
European (Non-Finnish)00.0absent
South Asian00.0absent
Other00.0absent

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:12522139, PubMed:12763021, PubMed:12740439, PubMed:12679784, PubMed:24941111). 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 (Probable). PSENEN modulates both endoproteolysis of presenilin and gamma-secretase activity (PubMed:12522139, PubMed:12763021, PubMed:12740439, PubMed:12679784, PubMed:24941111). {ECO:0000269|PubMed:12522139, ECO:0000269|PubMed:12679784, ECO:0000269|PubMed:12740439, ECO:0000269|PubMed:12763021, ECO:0000269|PubMed:24941111, ECO:0000305}.;

Intolerance Scores

RVIS EVS
0.1
RVIS percentile EVS
60.96

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.961

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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