NOTCH2
protein-codingnotch receptor 2, the group of Notch receptors
Gene summary
This gene encodes a member of the Notch family. Members of this Type 1 transmembrane protein family share structural characteristics including an extracellular domain consisting of multiple epidermal growth factor-like (EGF) repeats, and an intracellular domain consisting of multiple, different domain types. Notch family members play a role in a variety of developmental processes by controlling cell fate decisions. The Notch signaling network is an evolutionarily conserved intercellular signaling pathway which regulates interactions between physically adjacent cells. In Drosophilia, notch interaction with its cell-bound ligands (delta, serrate) establishes an intercellular signaling pathway that plays a key role in development. Homologues of the notch-ligands have also been identified in human, but precise interactions between these ligands and the human notch homologues remain to be determined. This protein is cleaved in the trans-Golgi network, and presented on the cell surface as a heterodimer. This protein functions as a receptor for membrane bound ligands, and may play a role in vascular, renal and hepatic development. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2011]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~189.2 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0012439
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0007057
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0007057
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0007057
Submitter: ClinGen
*NOTCH2* was first reported in relation to autosomal dominant Hajdu-Cheney syndrome-*NOTCH2* in 2011 (Simpson et al., 2011 PMID: 21378985). This condition is characterized by acroosteolysis of distal phalanges and generalized osteoporosis, associated with additional ossification anomalies, craniofacial dysmorphism, dental anomalies and a wide range of other characteristics. Hearing loss, renal cysts, and cardiovascular anomalies are variably present. Per criteria outlined by the ClinGen Lumping and Splitting guidelines, we found differences in molecular mechanism and phenotypic variability. Therefore, *NOTCH2* related phenotypes have been split into two disease entities, Alagille syndrome-*NOTCH2* and Hajdu-Cheney syndrome-*NOTCH2*. Hajdu-Cheney syndrome-*NOTCH2* has been lumped with serpentine fibula-polycystic kidney syndrome into a single entity, Hajdu-Cheney syndrome-*NOTCH2*, based on shared molecular mechanism and phenotypic spectrum. The split curation for autosomal dominant Alagille syndrome-*NOTCH2* has been handled separately. Thirty-one variants (truncating variants in exon 34 that disrupt the PEST domain) that have been reported in 31 probands in nine publications (PMIDs: 21378985, 21378989, 39748536, 27312922, 36079132, 23401378, 21681853, 35289498, 21793104) in Hajdu-Cheney syndrome-*NOTCH2* are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) was reached. The mechanism of pathogenicity is truncating variants in exon 34 which escape nonsense-mediated decay and disrupt the PEST domain (PMID: 21378985), which appear to act through a gain-of-function mechanism (PMID: 29149593). This gene-disease relationship is also supported by experimental evidence, including functional alterations in non-patient cells, altered expression in patient cells, and two mouse models (PMIDs: 39745791, 29149593, 20299358, 26627824). In summary, there is definitive evidence supporting the relationship between *NOTCH2* and autosomal dominant Hajdu-Cheney syndrome-*NOTCH2*. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Kidney Cystic and Ciliopathy Disorders GCEP on the meeting date April 14, 2025 (SOP Version 11).
Inheritance Pattern: AD
Disease ID:MONDO:0007318
Submitter: ClinGen
*NOTCH2* was first reported in relation to autosomal dominant Alagille syndrome-*NOTCH2* in 2006 (McDaniel et al., PMID: 16773578). Alagille syndrome-*NOTCH2* is a multisystem disorder with a high degree of variability in clinical manifestations and severity, even among members of the same family. Manifestations include, but are not limited to, bile duct paucity, congenital cardiac defects, butterfly vertebrae, posterior embryotoxon, characteristic facial features, and renal abnormalities. *NOTCH2* has been noted to be associated with the following disease entities: Alagille syndrome 2 (MIM: 610205), Hajdu-Cheney syndrome (MIM: 102500), and Serpentine Fibula-Polycystic Kidney Syndrome. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in molecular mechanisms and phenotypic variability. Therefore, Alagille syndrome-*NOTCH2* was split from the other two assertions, and Hajdu-Cheney syndrome and Serpentine Fibula-Polycystic Kidney Syndrome were lumped into a single entity, Hajdu-Cheney syndrome-*NOTCH2*, which has been curated separately. Hajdu-Cheney syndrome-*NOTCH2* is caused by protein truncating variants in exon 34 that escape nonsense-mediated decay and remove only the PEST domain, which are postulated to act through a gain of function mechanism. Alagille syndrome is caused by variants upstream of those implicated in Hajdu-Cheney syndrome, and the mechanism of pathogenicity appears to be haploinsufficiency. Seventeen variants (missense, nonsense, frameshift, large deletion, canonical splice site) that have been reported in 17 probands in 9 publications (PMIDs: 16773578, 31343788, 22209762, 26858187, 28776642, 36458146, 33077891, 36201396, 36447191) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. This gene-disease relationship is also supported by expression studies, and a mouse model (PMIDs: 15307138, 11171333). In summary, there is Definitive evidence supporting the relationship between *NOTCH2* and autosomal dominant Alagille syndrome-*NOTCH2*. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and upheld over time. This classification was approved by the ClinGen Kidney Cystic and Ciliopathy Disorders GCEP on the meeting date February 26, 2025 (SOP Version 11).
Inheritance Pattern: AD
Disease ID:MONDO:0007057
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0012439
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0007318
Submitter: Illumina
The NOTCH2 gene is located on chromosome 1 at 1p12 and encodes the notch receptor 2 protein, a single transmembrane domain protein integral to the conserved notch signalling pathway. Notch signalling occurs via cell to cell communication and is involved in determining the cellular fate of diverse cell types, which in turn regulates the homeostatsis of many tissue types. NOTCH2 was first reported in relation to autosomal dominant Alagille syndrome in 2006 (16773578; McDaniell et al. 2006). At least eight unique variants, including seven missense variants and one stop gained variant have been reported. Evidence supporting this gene-disease relationship includes case-level data, and experimental data. Variants in this gene have been reported in at least eight probands in three publications (16773578: McDaniell et al. 2006; 22209762: Kamath et al. 2012; 22488849; Lin et al. 2012). Variants in two cases occurred de novo. Mechanism of disease unclear, where variant level functional data is available, missense variants disrupted the Notch signalling pathway (NSP). This gene-disease relationship is supported by functional and animal model experimental data. The NOTCH1 ligand, JAG1 is associated with autosomal dominant Alagille syndrome (28794168: Siebel et al. 2017). NOTCH 2 is expressed in tissues consistent with the disease phenotype and is localised to cells adjacent to those expressing JAG1 (11171333: McCright et al. 2001) . Mice expressing a hypomorphic Notch2 allele recapitulate some features of Alagille syndrome, as do mice which a heterozygous for both the Notch2 hypomorphic allele and a JAG1 null allele (11171333: McCright et al. 2001; 11861489: McCright et al. 2002). In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged.
Inheritance Pattern: AD
Disease ID:MONDO:0007318
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0012439
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0007057
Submitter: Orphanet
Clinical Genomic Database (CGD)
Manifestation: Cardiovascular; Craniofacial; Endocrine; Gastrointestinal; Musculoskeletal; Neurologic; Ophthalmologic; Renal
Intervention: Cardiovascular; Gastrointestinal; Renal
Rationale: 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
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to NOTCH2 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_024408.4. 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.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 35 | 465 | 7 | 507 | ||
| missense | 4 | 12 | 1185 | 122 | 9 | 1332 |
| nonsense | 27 | 14 | 3 | 44 | ||
| start loss | 1 | 1 | 2 | |||
| frameshift | 25 | 28 | 12 | 1 | 66 | |
| splice donor/acceptor (+/-2bp) | 3 | 7 | 14 | 24 | ||
| Total | 59 | 61 | 1250 | 589 | 16 | 1975 |
Highest pathogenic variant AF is 0.000009345562
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_077719.2 | 34 | MANE Select | |
| Ensembl | ENSP00000256646.2 | 34 | MANE Select | |
| RefSeq | NP_001186930.1 | 22 | Standard | |
| Ensembl | ENSP00000492223.1 | 3 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| notch2 | Danio rerio | Structure: pancreatic B cell Quality: decreased area abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- 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)
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
Molecular Function
- calcium ion binding
- protein binding
- signaling receptor activity
Cellular Component
- Golgi membrane
- extracellular region
- nucleus
- nucleoplasm
- endoplasmic reticulum membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000256646
- Coding exons
- 34
- Length
- 158065
- Individuals with no LoFs
- 125732
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 16
- Defined
- 125748
- p
- 0.0000636
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 3.50 | 1000 | 1.36e+3 | 0.733 | 0.0000775 | 16313 |
| Missense (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 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00018 | 0.00018 | rare |
| Latino/Admixed American | 0.000029 | 0.000029 | rare |
| Ashkenazi Jewish | 0.000099 | 0.000099 | rare |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.000071 | 0.000070 | rare |
| South Asian | 0.000098 | 0.000098 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- 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}.;
Recessive Scores
- pRec
- 0.438
Intolerance Scores
- LoFtool
- 0.0156
- RVIS EVS
- -1.82
- RVIS percentile EVS
- 2.15
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.973
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |