NOTCH2

notch receptor 2, the group of Notch receptors

Basic information

Region (hg38): 1:119911553-120100779

Links

ENSG00000134250 ∙ NCBI:4853 ∙ OMIM:600275 ∙ HGNC:7882 ∙ Uniprot:Q04721 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• Acroosteolysis dominant type (Definitive), mode of inheritance: AD
• Alagille syndrome (Moderate), mode of inheritance: AD
• Acroosteolysis dominant type (Supportive), mode of inheritance: AD
• Acroosteolysis dominant type (Strong), mode of inheritance: AD
• Alagille syndrome due to a NOTCH2 point mutation (Strong), mode of inheritance: AD
• Alagille syndrome due to a NOTCH2 point mutation (Strong), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Alagille syndrome 2	AD	Cardiovascular; Gastrointestinal; Renal	The condition may not be clinically apparent; for hepatic complications, medications (eg, ursodeoxycholic acid, cholestyramine), and, when necessary, partial external biliary diversion may be beneficial; other treatments, such as fat-soluble vitamin supplementation may be beneficial; Surveillance for other manifestations, including cardiac and renal manifestations (such as renal tubular acidosis, which has been described in affected individuals), may be beneficial in order to allow early diagnosis and treatment and/or preventive measures	Cardiovascular; Craniofacial; Endocrine; Gastrointestinal; Musculoskeletal; Neurologic; Ophthalmologic; Renal	18918373; 14303950; 8723560; 11343321; 16773578; 17159511; 20301450; 21378989; 21681853; 21378985; 21712856; 21793104; 21934706; 22209762; 22488849; 23117206; 23389697; 23401378; 23566664; 24265536

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the NOTCH2 gene.

• Hajdu-Cheney syndrome (25 variants)
• not provided (16 variants)
• Alagille syndrome due to a NOTCH2 point mutation (2 variants)
• NOTCH2-related disorder (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the NOTCH2 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			23	251	15	289
missense	1	4	699	27	12	743
nonsense	17	5	1			23
start loss					1	1
frameshift	22	10		1		33
inframe indel			7			7
splice donor/acceptor (+/-2bp)	1	2	3			6
splice region			22	28	2	52
non coding			8	137	62	207
Total	41	21	741	416	90

Highest pathogenic variant AF is 0.00000657

Variants in NOTCH2

This is a list of pathogenic ClinVar variants found in the NOTCH2 region.

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

Position	Type	Phenotype	Significance	ClinVar
1-119915297-T-G		NOTCH2-related disorder	Likely benign (Sep 04, 2020)
1-119915306-T-G			Uncertain significance (May 07, 2018)
1-119915309-C-G		Hajdu-Cheney syndrome	Likely benign (Oct 28, 2022)
1-119915309-C-T		Hajdu-Cheney syndrome • NOTCH2-related disorder	Conflicting classifications of pathogenicity (Jan 26, 2024)
1-119915310-G-A		NOTCH2-related disorder	Uncertain significance (Jan 19, 2024)
1-119915317-C-T		Hajdu-Cheney syndrome	Uncertain significance (May 19, 2022)
1-119915320-G-T		Hajdu-Cheney syndrome • Inborn genetic diseases	Uncertain significance (Sep 22, 2023)
1-119915322-ATGT-A			Uncertain significance (May 05, 2020)
1-119915332-G-A		Hajdu-Cheney syndrome	Uncertain significance (Jul 25, 2023)
1-119915332-G-C		Hajdu-Cheney syndrome	Uncertain significance (Jan 26, 2023)
1-119915333-T-C		Hajdu-Cheney syndrome	Likely benign (Jan 22, 2023)
1-119915345-C-T		Hajdu-Cheney syndrome • Alagille syndrome due to a NOTCH2 point mutation;Hajdu-Cheney syndrome • NOTCH2-related disorder	Uncertain significance (Aug 01, 2023)
1-119915346-A-G		Hajdu-Cheney syndrome	Uncertain significance (Aug 30, 2023)
1-119915354-C-G		Hajdu-Cheney syndrome	Likely benign (Mar 04, 2022)
1-119915354-C-T		Hajdu-Cheney syndrome	Conflicting classifications of pathogenicity (Nov 22, 2022)
1-119915358-G-A		Hajdu-Cheney syndrome	Uncertain significance (Dec 10, 2023)
1-119915364-C-T		Hajdu-Cheney syndrome	Uncertain significance (Oct 18, 2021)
1-119915366-C-A		Hajdu-Cheney syndrome	Uncertain significance (Aug 20, 2022)
1-119915366-C-G			Uncertain significance (Apr 06, 2017)
1-119915369-A-G		Hajdu-Cheney syndrome	Likely benign (Jul 29, 2022)
1-119915369-A-T		Hajdu-Cheney syndrome	Likely benign (Dec 27, 2022)
1-119915380-C-A		Alagille syndrome due to a NOTCH2 point mutation;Hajdu-Cheney syndrome • Hajdu-Cheney syndrome • Inborn genetic diseases	Conflicting classifications of pathogenicity (Sep 13, 2023)
1-119915381-A-T		not specified • Hajdu-Cheney syndrome	Benign (Jan 31, 2024)
1-119915384-C-A		Hajdu-Cheney syndrome • NOTCH2-related disorder	Likely benign (Jan 18, 2024)
1-119915384-C-T		Hajdu-Cheney syndrome	Conflicting classifications of pathogenicity (Dec 25, 2022)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
NOTCH2	protein_coding	protein_coding	ENST00000256646	34	158065

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.00	8.39e-13	125732	0	16	125748	0.0000636

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	3.50	1000	1.36e+3	0.733	0.0000775	16313
Missense in Polyphen		324	625.72	0.5178		7485
Synonymous	-0.438	518	505	1.02	0.0000277	4733
Loss of Function	8.83	6	102	0.0586	0.00000544	1271

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000214	0.000213
Ashkenazi Jewish	0.0000994	0.0000992
East Asian	0.00	0.00
Finnish	0.00	0.00
European (Non-Finnish)	0.0000707	0.0000703
Middle Eastern	0.00	0.00
South Asian	0.0000980	0.0000980
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Functions as a receptor for membrane-bound ligands Jagged-1 (JAG1), Jagged-2 (JAG2) and Delta-1 (DLL1) to regulate cell-fate determination. Upon ligand activation through the released notch intracellular domain (NICD) it forms a transcriptional activator complex with RBPJ/RBPSUH and activates genes of the enhancer of split locus (PubMed:21378985, PubMed:21378989). Affects the implementation of differentiation, proliferation and apoptotic programs (By similarity). Involved in bone remodeling and homeostasis. In collaboration with RELA/p65 enhances NFATc1 promoter activity and positively regulates RANKL- induced osteoclast differentiation (PubMed:29149593). Positively regulates self-renewal of liver cancer cells (PubMed:25985737). {ECO:0000250|UniProtKB:O35516, ECO:0000269|PubMed:21378985, ECO:0000269|PubMed:21378989, ECO:0000269|PubMed:25985737, ECO:0000269|PubMed:29149593}.
• Disease: DISEASE: Alagille syndrome 2 (ALGS2) [MIM:610205]: A form of Alagille syndrome, an autosomal dominant multisystem disorder. It is clinically defined by hepatic bile duct paucity and cholestasis in association with cardiac, skeletal, and ophthalmologic manifestations. There are characteristic facial features and less frequent clinical involvement of the renal and vascular systems. {ECO:0000269|PubMed:16773578}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Hajdu-Cheney syndrome (HJCYS) [MIM:102500]: A rare, autosomal dominant skeletal disorder characterized by the association of facial anomalies, acro-osteolysis, general osteoporosis, insufficient ossification of the skull, and periodontal disease (premature loss of permanent teeth). Other features include cleft palate, congenital heart defects, polycystic kidneys, orthopedic problems and anomalies of the genitalia, intestines and eyes. {ECO:0000269|PubMed:21378985, ECO:0000269|PubMed:21378989, ECO:0000269|PubMed:21681853, ECO:0000269|PubMed:21712856, ECO:0000269|PubMed:21793104, ECO:0000269|PubMed:23389697, ECO:0000269|PubMed:29149593}. Note=The disease is caused by mutations affecting the gene represented in this entry. NOTCH2 nonsense and frameshift mutations associated with Hajdu-Cheney syndrome cluster to the last coding exon of the gene. Mutant mRNA products escape nonsense-mediated decay and the resulting truncated NOTCH2 proteins act in a gain-of-function manner (PubMed:21378989). The pathological mechanism at cellular level involves disruption of a high affinity degron recognized by FBXW7 at the C-terminus, loss of interaction with FBXW7, reduced ubiquitination and degradation, and increased NOTCH2 levels. Bone marrow cells derived from HJCYS patients have an enhanced capacity of osteoclastogenesis due to sustained NOTCH2 activity (PubMed:29149593). {ECO:0000269|PubMed:21378989, ECO:0000269|PubMed:29149593}.
• Pathway: Breast cancer - Homo sapiens (human);Thyroid hormone signaling pathway - Homo sapiens (human);Th1 and Th2 cell differentiation - Homo sapiens (human);MicroRNAs in cancer - Homo sapiens (human);Pathways in cancer - Homo sapiens (human);Notch signaling pathway - Homo sapiens (human);Human papillomavirus infection - Homo sapiens (human);NOTCH-Core;miR-targeted genes in epithelium - TarBase;miR-targeted genes in lymphocytes - TarBase;miR-targeted genes in muscle cell - TarBase;Neural Crest Differentiation;Notch Signaling Pathway;Pre-NOTCH Expression and Processing;Canonical and Non-canonical Notch signaling;Role of Osx and miRNAs in tooth development;EMT transition in Colorectal Cancer;Notch Signaling Pathway;Notch Signaling Pathway;Notch;Signal Transduction;Gene expression (Transcription);Generic Transcription Pathway;RNA Polymerase II Transcription;Receptor-ligand binding initiates the second proteolytic cleavage of Notch receptor;Notch-HLH transcription pathway;Notch;NICD traffics to nucleus;Pre-NOTCH Processing in the Endoplasmic Reticulum;Pre-NOTCH Processing in Golgi;Pre-NOTCH Expression and Processing;NOTCH2 intracellular domain regulates transcription;Signaling by NOTCH2;Signaling by NOTCH;A third proteolytic cleavage releases NICD;NOTCH2 Activation and Transmission of Signal to the Nucleus;Notch signaling pathway (Consensus)

Recessive Scores

• pRec: 0.438

Intolerance Scores

• loftool: 0.0156
• rvis_EVS: -1.82
• rvis_percentile_EVS: 2.15

Haploinsufficiency Scores

• pHI: 0.953
• hipred: Y
• hipred_score: 0.685
• ghis: 0.551

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.973

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Notch2
• Phenotype: cellular phenotype; homeostasis/metabolism phenotype; craniofacial phenotype; muscle phenotype; endocrine/exocrine gland phenotype; taste/olfaction 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; embryo phenotype; skeleton phenotype; renal/urinary system phenotype; immune system phenotype; vision/eye phenotype; limbs/digits/tail 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); digestive/alimentary phenotype; neoplasm; pigmentation phenotype; reproductive 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); 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); liver/biliary system phenotype; respiratory system phenotype

Zebrafish Information Network

• Gene name: notch2
• Affected structure: pancreatic B cell
• Phenotype tag: abnormal
• Phenotype quality: decreased area

Gene ontology

• Biological process: cell fate determination;marginal zone B cell differentiation;pulmonary valve morphogenesis;regulation of transcription, DNA-templated;transcription initiation from RNA polymerase II promoter;apoptotic process;cell cycle arrest;Notch signaling pathway;multicellular organism development;nervous system development;animal organ morphogenesis;negative regulation of gene expression;stem cell population maintenance;hemopoiesis;negative regulation of apoptotic process;negative regulation of growth rate;positive regulation of Ras protein signal transduction;bone remodeling;atrial septum morphogenesis;Notch signaling involved in heart development;positive regulation of ERK1 and ERK2 cascade;regulation of osteoclast development
• Cellular component: Golgi membrane;extracellular region;nucleus;nucleoplasm;endoplasmic reticulum membrane;plasma membrane;integral component of plasma membrane;cell surface;membrane;receptor complex
• Molecular function: calcium ion binding;protein binding;signaling receptor activity