PSENEN

presenilin enhancer, gamma-secretase subunit

Basic information

Region (hg38): 19:35745599-35747519

Links

ENSG00000205155 ∙ NCBI:55851 ∙ OMIM:607632 ∙ HGNC:30100 ∙ Uniprot:Q9NZ42 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• acne inversa, familial, 2 (Strong), mode of inheritance: AD
• Dowling-Degos disease (Supportive), mode of inheritance: AD
• acne inversa, familial, 2 (Strong), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Acne inversa, familial, 2, with or without Dowling-Degos disease	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; 28287404; 28601418

ClinVar

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

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the PSENEN 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				6	1	7
missense			14			14
nonsense			1			1
start loss						0
frameshift			1			1
inframe indel						0
splice donor/acceptor (+/-2bp)						0
splice region			1	1		2
non coding				8	1	9
Total	0	0	16	14	2

Variants in PSENEN

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

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

Position	Type	Phenotype	Significance	ClinVar
19-35745610-A-G		PSENEN-related disorder	Likely benign (Oct 12, 2023)
19-35745965-T-A		Acne inversa, familial, 2	Pathogenic (Dec 01, 2017)
19-35745970-C-T			Benign (Jul 21, 2023)
19-35745987-C-T			Likely benign (Dec 02, 2022)
19-35745994-A-G			Uncertain significance (Nov 27, 2021)
19-35746001-A-G			Likely benign (May 23, 2023)
19-35746001-ATCGCTAGGG-A			Likely benign (Feb 10, 2022)
19-35746005-C-T			Likely benign (Oct 24, 2022)
19-35746008-G-C		Acne inversa, familial, 2	Benign (Jan 31, 2024)
19-35746008-G-T			Likely benign (Sep 06, 2023)
19-35746010-G-A			Likely benign (Sep 14, 2023)
19-35746417-AG-A		Acne inversa, familial, 2	Pathogenic (Nov 19, 2010)
19-35746417-A-AG		Acne inversa, familial, 2	Pathogenic (Dec 01, 2017)
19-35746418-G-C		Acne inversa, familial, 2	Pathogenic (Dec 01, 2017)
19-35746422-G-A			Uncertain significance (Nov 18, 2023)
19-35746428-C-G			Uncertain significance (Aug 04, 2023)
19-35746432-C-G			Uncertain significance (Nov 24, 2023)
19-35746484-C-T			Uncertain significance (Jan 16, 2023)
19-35746494-C-A			Uncertain significance (Jan 18, 2021)
19-35746535-G-T			Likely benign (Oct 23, 2023)
19-35746692-C-G			Likely benign (Nov 07, 2023)
19-35746697-T-C			Likely benign (Mar 01, 2022)
19-35746704-A-G			Likely benign (Feb 21, 2023)
19-35746706-A-G		Acne inversa, familial, 2	Pathogenic (Dec 01, 2017)
19-35746709-T-G			Uncertain significance (May 26, 2021)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
PSENEN	protein_coding	protein_coding	ENST00000587708	3	1897

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.876	0.122	0	0	0	0	0.00

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.644	41	54.4	0.754	0.00000298	646
Missense in Polyphen		11	20.983	0.52423		258
Synonymous	1.13	14	20.5	0.682	9.10e-7	201
Loss of Function	2.42	0	6.81	0.00	3.80e-7	61

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00	0.00
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.00	0.00
European (Non-Finnish)	0.00	0.00
Middle Eastern	0.00	0.00
South Asian	0.00	0.00
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: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}.
• Pathway: Alzheimer,s disease - Homo sapiens (human);Notch signaling pathway - Homo sapiens (human);NOTCH-Core;Alzheimers Disease;Notch Signaling Pathway;Notch;Disease;Signal Transduction;DroToll-like;Notch;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;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)

Intolerance Scores

• rvis_EVS: 0.1
• rvis_percentile_EVS: 60.96

Haploinsufficiency Scores

• pHI: 0.257
• hipred: Y
• hipred_score: 0.672
• ghis: 0.568

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.961

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Psenen
• 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)

Zebrafish Information Network

• Gene name: psenen
• Affected structure: primary motor neuron
• Phenotype tag: abnormal
• Phenotype quality: irregular spatial pattern

Gene ontology

• Biological process: membrane protein ectodomain proteolysis;Notch receptor processing;protein processing;amyloid-beta formation;Notch receptor processing, ligand-dependent;amyloid precursor protein metabolic process;amyloid precursor protein catabolic process;positive regulation of catalytic activity
• Cellular component: endoplasmic reticulum;endoplasmic reticulum membrane;Golgi apparatus;plasma membrane;integral component of plasma membrane;endosome membrane;integral component of membrane;Golgi cisterna membrane;gamma-secretase complex
• Molecular function: protein binding