PSEN2

presenilin 2, the group of Peptidase family A22

Basic information

Region (hg38): 1:226870183-226927726

Previous symbols: [ "AD4" ]

Links

ENSG00000143801 ∙ NCBI:5664 ∙ OMIM:600759 ∙ HGNC:9509 ∙ Uniprot:P49810 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• Alzheimer disease 4 (Strong), mode of inheritance: AD
• early-onset autosomal dominant Alzheimer disease (Supportive), mode of inheritance: AD
• familial isolated dilated cardiomyopathy (Supportive), mode of inheritance: AD
• Alzheimer disease 4 (Strong), mode of inheritance: AD
• dilated cardiomyopathy (Limited), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Cardiomyopathy, dilated, 1V; Peripartum/pregnancy-associated cardiomyopathy	AD	Cardiovascular; Obstetric	Preventive measures and medical management may be helpful to help decrease morbidity; Precautions/surveillance may be beneficial prior to/during pregnancy	Cardiovascular; Neurologic; Obstetric	7638622; 7651536; 9521418; 10822446; 11723295; 14681895; 12925374; 14623725; 17186461; 18427071; 20458009; 20457965

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the PSEN2 gene.

• Alzheimer disease 4 (172 variants)
• not provided (103 variants)
• Dilated cardiomyopathy 1V (67 variants)
• not specified (25 variants)
• Alzheimer disease 4;Dilated cardiomyopathy 1V (9 variants)
• Inborn genetic diseases (8 variants)
• PSEN2-related condition (4 variants)
• Alzheimer disease (3 variants)
• Dilated cardiomyopathy 1V;Alzheimer disease 4 (3 variants)
• Vascular dementia (1 variants)
• Huntington disease-like syndrome (1 variants)
• Primary dilated cardiomyopathy (1 variants)
• Dilated Cardiomyopathy, Dominant (1 variants)
• Early-onset autosomal dominant Alzheimer disease (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the PSEN2 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			5	53	5	63
missense	1	1	72	8	1	83
nonsense			1			1
start loss			1			1
frameshift			3			3
inframe indel						0
splice donor/acceptor (+/-2bp)		1				1
splice region			2	2		4
non coding			18	27	28	73
Total	1	2	100	88	34

Variants in PSEN2

This is a list of pathogenic ClinVar variants found in the PSEN2 region.

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

Position	Type	Phenotype	Significance	ClinVar
1-226870599-C-T		Early-onset autosomal dominant Alzheimer disease • Dilated Cardiomyopathy, Dominant	Likely benign (Jun 14, 2016)
1-226870643-A-G		Dilated cardiomyopathy 1V • Alzheimer disease 4	Benign (Jan 12, 2018)
1-226871147-A-G			Uncertain significance (Jul 10, 2021)
1-226871273-A-G		Dilated cardiomyopathy 1V • Alzheimer disease 4	Likely benign (Apr 28, 2017)
1-226871333-C-A		Alzheimer disease 4 • Dilated cardiomyopathy 1V	Uncertain significance (Feb 09, 2018)
1-226871333-C-T		Alzheimer disease 4 • Dilated cardiomyopathy 1V	Uncertain significance (Jan 13, 2018)
1-226871336-C-T		Alzheimer disease 4 • Dilated cardiomyopathy 1V	Benign (Jan 12, 2018)
1-226875387-C-T		Dilated cardiomyopathy 1V • Alzheimer disease 4	Uncertain significance (Apr 27, 2017)
1-226875427-A-G		Alzheimer disease 4 • Dilated cardiomyopathy 1V	Uncertain significance (Jan 13, 2018)
1-226875435-G-A		Alzheimer disease 4 • Dilated cardiomyopathy 1V	Uncertain significance (Jan 13, 2018)
1-226875489-T-C		Alzheimer disease 4 • Dilated cardiomyopathy 1V	Uncertain significance (Jan 13, 2018)
1-226875528-C-T		Alzheimer disease 4 • Dilated cardiomyopathy 1V	Benign (Jan 13, 2018)
1-226881909-T-G		PSEN2-related disorder	Uncertain significance (May 17, 2023)
1-226881932-A-G			Uncertain significance (Jun 24, 2013)
1-226881936-AG-A			Uncertain significance (Feb 11, 2021)
1-226881945-T-C		Dilated cardiomyopathy 1V • Alzheimer disease 4 • Inborn genetic diseases	Uncertain significance (Oct 12, 2022)
1-226881956-C-T			Uncertain significance (Jun 24, 2013)
1-226881960-C-T		Vascular dementia • not specified	Uncertain significance (Aug 04, 2023)
1-226881961-G-A		Alzheimer disease 4	Likely benign (Mar 23, 2022)
1-226881973-G-A		not specified • Alzheimer disease 4 • PSEN2-related disorder	Likely benign (May 23, 2023)
1-226881976-T-C		not specified • Dilated cardiomyopathy 1V • Alzheimer disease 4	Benign (Feb 01, 2024)
1-226881987-C-T		Alzheimer disease 4 • Inborn genetic diseases	Uncertain significance (Dec 06, 2022)
1-226881988-GC-AA		Alzheimer disease 4	Uncertain significance (Aug 30, 2021)
1-226881991-G-A			Likely benign (Jun 05, 2018)
1-226881992-C-T		Alzheimer disease 4 • Inborn genetic diseases • Alzheimer disease 4;Dilated cardiomyopathy 1V	Uncertain significance (Oct 03, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
PSEN2	protein_coding	protein_coding	ENST00000366783	10	25922

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.000537	0.994	125721	0	27	125748	0.000107

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.404	254	273	0.931	0.0000168	2913
Missense in Polyphen		88	106.14	0.82908		1218
Synonymous	-1.77	145	120	1.21	0.00000866	904
Loss of Function	2.44	9	21.1	0.426	9.11e-7	255

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000116	0.000116
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.00	0.00
European (Non-Finnish)	0.000141	0.000141
Middle Eastern	0.00	0.00
South Asian	0.000229	0.000229
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Probable catalytic 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). Requires the other members of the gamma-secretase complex to have a protease activity. May play a role in intracellular signaling and gene expression or in linking chromatin to the nuclear membrane. May function in the cytoplasmic partitioning of proteins. {ECO:0000269|PubMed:10497236, ECO:0000269|PubMed:10652302}.
• Disease: DISEASE: Alzheimer disease 4 (AD4) [MIM:606889]: A familial early- onset form of Alzheimer disease. Alzheimer disease is a neurodegenerative disorder characterized by progressive dementia, loss of cognitive abilities, and deposition of fibrillar amyloid proteins as intraneuronal neurofibrillary tangles, extracellular amyloid plaques and vascular amyloid deposits. The major constituents of these plaques are neurotoxic amyloid-beta protein 40 and amyloid-beta protein 42, that are produced by the proteolysis of the transmembrane APP protein. The cytotoxic C- terminal fragments (CTFs) and the caspase-cleaved products, such as C31, are also implicated in neuronal death. {ECO:0000269|PubMed:10631141, ECO:0000269|PubMed:10732806, ECO:0000269|PubMed:22503161, ECO:0000269|PubMed:7638622, ECO:0000269|PubMed:7651536, ECO:0000269|PubMed:9384602}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Cardiomyopathy, dilated 1V (CMD1V) [MIM:613697]: A disorder characterized by ventricular dilation and impaired systolic function, resulting in congestive heart failure and arrhythmia. Patients are at risk of premature death. {ECO:0000269|PubMed:17186461}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Neurotrophin signaling pathway - Homo sapiens (human);Alzheimer,s disease - Homo sapiens (human);Notch signaling pathway - Homo sapiens (human);NOTCH-Core;Alzheimers Disease;Notch Signaling Pathway;Canonical and Non-canonical Notch signaling;Notch Signaling Pathway;Notch Signaling Pathway;Notch;Disease;Signal Transduction;hiv-1 nef: negative effector of fas and tnf;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;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;Cell death signalling via NRAGE, NRIF and NADE;LKB1 signaling events;Activated NOTCH1 Transmits Signal to the Nucleus (Consensus)

Recessive Scores

• pRec: 0.664

Intolerance Scores

• loftool: 0.0232
• rvis_EVS: -1.02
• rvis_percentile_EVS: 8.04

Haploinsufficiency Scores

• pHI: 0.642
• hipred: Y
• hipred_score: 0.763
• ghis: 0.548

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.761

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Psen2
• Phenotype: homeostasis/metabolism phenotype; cellular phenotype; craniofacial phenotype; endocrine/exocrine gland phenotype; growth/size/body region 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); embryo phenotype; renal/urinary system phenotype; immune system phenotype; vision/eye phenotype; digestive/alimentary phenotype; 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); 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); hematopoietic system phenotype; 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); respiratory system phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan)

Zebrafish Information Network

• Gene name: psen2
• Affected structure: neuron
• Phenotype tag: abnormal
• Phenotype quality: increased amount

Gene ontology

• Biological process: response to hypoxia;membrane protein ectodomain proteolysis;calcium ion transport;Notch receptor processing;protein processing;Notch receptor processing, ligand-dependent;intracellular signal transduction;amyloid precursor protein catabolic process;positive regulation of catalytic activity;amyloid-beta metabolic process
• Cellular component: Golgi membrane;kinetochore;nucleus;nuclear inner membrane;endoplasmic reticulum;endoplasmic reticulum membrane;Golgi apparatus;centrosome;plasma membrane;integral component of plasma membrane;cell cortex;membrane;apical plasma membrane;Z disc;protein-containing complex;neuronal cell body;perinuclear region of cytoplasm;integral component of presynaptic membrane
• Molecular function: endopeptidase activity;aspartic-type endopeptidase activity;protein binding;aspartic endopeptidase activity, intramembrane cleaving