NOD2
protein-codingnucleotide binding oligomerization domain containing 2, the group of Caspase recruitment domain containing|NLR family
Gene summary
This gene is a member of the Nod1/Apaf-1 family and encodes a protein with two caspase recruitment (CARD) domains and six leucine-rich repeats (LRRs). The protein is primarily expressed in the peripheral blood leukocytes. It plays a role in the immune response to intracellular bacterial lipopolysaccharides (LPS) by recognizing the muramyl dipeptide (MDP) derived from them and activating the NFKB protein. Mutations in this gene have been associated with Crohn disease and Blau syndrome. Alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. [provided by RefSeq, Jun 2014]
- IBD1
- CARD15
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~39.5 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0008523
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0008523
Submitter: Genomics England PanelApp
Inheritance Pattern: AD
Disease ID:MONDO:0008523
Submitter: Illumina
The NOD2 gene is located on chromosome 16 at 16q12.1 and encodes the nucleotide-binding oligomerization domain-containing protein 2, a member of the NOD-like receptor family. NOD2 is a cytoplasmic pattern recognition receptor and plays an important role in regulating the innate immune response. The NOD2 gene was first reported in relation to autosomal dominant Blau syndrome in 2001 (11528384: Miceli-Richard et al. 2001). At least 20 unique missense variants have been reported in clinical cases, with up to 80% of Blau syndrome associated with two recurrent NOD2 variants; p.Arg334Trp and p.Arg334Gln (25182201: Caso et al. 2014). Evidence supporting this gene-disease relationship includes case-level data, segregation data and experimental data. Variants in this gene have been reported in at least nineteen probands in twelve publications (11528384; 15459013; 19116920; 19479837; 28721627; 28721627; 12428248; 17916199; 20084402; 31543536; 31803699; 17207093). Wang et al. (12428248: Wang et al. 2002) performed linkage analysis on ten families with Blau syndrome and reported a combined LOD score of 5.67. De novo variants have also been reported. The mechanism of disease is unknown, in vitro experiments suggest variants lead to a gain of function and ligand independent activation of NOD2 (25093298), however patient cell and mouse model data suggest a downregulation of NOD2 signalling pathways. This gene-disease relationship is supported by data from patient cells which point to a disruption of NOD2 signalling pathways (21296813; 20052476; 20052476; 20052476; 28587749). Mouse models also showed partial recapitulation of aspects of disease (25429073; 21296813). In summary, NOD2 is definitively associated with autosomal dominant Blau syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.
Inheritance Pattern: Unknown
Disease ID:MONDO:0009960
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0008523
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0008523
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0008523
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0008523
Submitter: ClinGen
The NOD2 gene is located on chromosome 16 at 16q12.1 and encodes the nucleotide-binding oligomerization domain-containing protein 2, a member of the NOD-like receptor family. NOD2 is a cytoplasmic pattern recognition receptor and plays an important role in regulating the innate immune response. The NOD2 gene was first reported in relation to autosomal dominant Blau syndrome in 2001 (Miceli-Richard et al., PMID 11528384). At least 20 unique missense variants have been reported in clinical cases with up to 80% of Blau syndrome associated with two recurrent NOD2 variants: p.Arg334Trp and p.Arg334Gln (Cantarini et al., 2014 PMID 25182201). Evidence supporting this gene-disease relationship includes case-level data, segregation data and experimental data. Variants in this gene have been reported in at least nineteen probands in twelve publications (Hugot et al., 2001 PMID 11528384; Miyachi et al., 2005 15459013; Nakahata et al., 2009 PMID 19116920; Wouters et al., 2009 PMID 19479837; Shen et al., 2017 PMID 28721627; Williams et al., 2002 PMID 12428248; Santos-Juanes et al., 2007 PMID 17916199; Cirak et al., 2010 PMID 20084402; Pramono et al., 2019 PMID 31543536; Li et al., 2019 PMID 31803699; Nielsen et al., 2016 PMID 17207093). Wang et al. (2002 PMID 12428248) performed linkage analysis on ten families with Blau syndrome and reported a combined LOD score of 5.67. De novo variants have also been reported. The mechanism of disease is unknown. In vitro experiments suggest variants lead to a gain of function and ligand independent activation of NOD2 (Monie et al., 2014 PMID 25093298); however, patient cell and mouse model data suggest a downregulation of NOD2 signalling pathways. This gene-disease association is supported by data from patient cells which point to a disruption of NOD2 signalling pathways (Rosenbaum et al., 2011 PMID 21296813; Lee et al., 2010 PMID 20052476; Saito et al., 2017 PMID 28587749). Mouse models also showed partial recapitulation of aspects of disease (Davey et al., 2015; PMID 21296813). In summary, NOD2 is definitively associated with autosomal dominant Blau syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.
Clinical Genomic Database (CGD)
Manifestation: Allergy/Immunology/Infectious; Dermatologic; Musculoskeletal; Ophthalmologic; Pulmonary
Intervention: Allergy/Immunology/Infectious
Rationale: In Blau syndrome and Yao syndrome, individuals have been described as responding to medical management (eg, TNF-alpha or IL1B inhibitory medications); Bi-allelic variants result in a ~40-fold higher relative risk of Crohn disease, and individuals may benefit from early diagnosis and management
Comments: Variants may also be related to susceptibility to Yao syndrome
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to NOD2 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_001370466.1. 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 | 12 | 291 | 3 | 306 | ||
| missense | 13 | 8 | 564 | 111 | 8 | 704 |
| nonsense | 1 | 32 | 33 | |||
| start loss | 1 | 1 | ||||
| frameshift | 2 | 25 | 27 | |||
| splice donor/acceptor (+/-2bp) | 1 | 10 | 2 | 13 | ||
| Total | 14 | 11 | 644 | 404 | 11 | 1084 |
Highest pathogenic variant AF is 0.000017795568
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_001357395.1 | 11 | MANE Select | |
| Ensembl | ENSP00000495993.1 | 11 | MANE Select | |
| RefSeq | NP_001280486.1 | 11 | Standard | |
| RefSeq | NP_071445.1 | 12 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Inflammatory bowel disease (IBD) - Homo sapiens (human)
- TNF signaling pathway - Homo sapiens (human)
- NOD-like receptor signaling pathway - Homo sapiens (human)
- Tuberculosis - Homo sapiens (human)
- Shigellosis - Homo sapiens (human)
Biological Process
- activation of MAPK activity
- cytokine production involved in immune response
- cytokine secretion involved in immune response
- positive regulation of dendritic cell antigen processing and presentation
- positive regulation of dendritic cell cytokine production
Molecular Function
- actin binding
- protein binding
- ATP binding
- enzyme binding
- protein kinase binding
Cellular Component
- cytoplasm
- mitochondrion
- Golgi apparatus
- cytosol
- cytoskeleton
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000300589
- Coding exons
- 12
- Length
- 39475
- Individuals with no LoFs
- 121887
- Homozygous LoFs
- 110
- Heterozygous LoFs
- 3751
- Defined
- 125748
- p
- 0.0155
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | -0.453 | 616 | 585 | 1.05 | 0.0000368 | 6705 |
| Missense (PolyPhen) | 189 | 191.08 | 0.98913 | 2454 | ||
| Synonymous | -2.44 | 313 | 263 | 1.19 | 0.0000171 | 2180 |
| Loss of Function | -0.360 | 44 | 41.5 | 1.06 | 0.00000218 | 451 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.0037 | 0.0036 | notable |
| Latino/Admixed American | 0.0099 | 0.0099 | notable |
| Ashkenazi Jewish | 0.035 | 0.034 | notable |
| East Asian | 0.00022 | 0.00022 | rare |
| Finnish | 0.016 | 0.016 | notable |
| European (Non-Finnish) | 0.024 | 0.023 | notable |
| South Asian | 0.0022 | 0.0022 | notable |
| Other | 0.017 | 0.017 | notable |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Involved in gastrointestinal immunity. Upon stimulation by muramyl dipeptide (MDP), a fragment of bacterial peptidoglycan, binds the proximal adapter receptor-interacting RIPK2, which recruits ubiquitin ligases as XIAP, BIRC2, BIRC3, INAVA and the LUBAC complex, triggering activation of MAP kinases and activation of NF-kappa-B signaling. This in turn leads to the transcriptional activation of hundreds of genes involved in immune response. Required for MDP-induced NLRP1-dependent CASP1 activation and IL1B release in macrophages (PubMed:18511561). Component of an autophagy-mediated antibacterial pathway together with ATG16L1 (PubMed:20637199). Plays also a role in sensing single-stranded RNA (ssRNA) from viruses. Interacts with mitochondrial antiviral signaling/MAVS, leading to activation of interferon regulatory factor-3/IRF3 and expression of type I interferon (PubMed:19701189). {ECO:0000269|PubMed:18511561, ECO:0000269|PubMed:19701189, ECO:0000269|PubMed:20637199, ECO:0000269|PubMed:23806334, ECO:0000269|PubMed:28436939}.;
- Disease
- DISEASE: Blau syndrome (BLAUS) [MIM:186580]: An autosomal dominant inflammatory disorder characterized by the formation of immune granulomas invading the skin, joints and eye. Other organs may be involved. Clinical manifestations are variable and include early- onset granulomatous arthritis, uveitis and skin rash. Blindness, joint destruction and visceral involvement have been reported in severe cases. {ECO:0000269|PubMed:11528384, ECO:0000269|PubMed:15459013, ECO:0000269|PubMed:15812565, ECO:0000269|PubMed:19116920, ECO:0000269|PubMed:19169908, ECO:0000269|PubMed:19359344, ECO:0000269|PubMed:19479837, ECO:0000269|PubMed:20199415, ECO:0000269|PubMed:24960071, ECO:0000269|PubMed:25093298, ECO:0000269|PubMed:25692065, ECO:0000269|PubMed:25724124, ECO:0000269|PubMed:27812135}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Inflammatory bowel disease 1 (IBD1) [MIM:266600]: A chronic, relapsing inflammation of the gastrointestinal tract with a complex etiology. It is subdivided into Crohn disease and ulcerative colitis phenotypes. Crohn disease may affect any part of the gastrointestinal tract from the mouth to the anus, but most frequently it involves the terminal ileum and colon. Bowel inflammation is transmural and discontinuous; it may contain granulomas or be associated with intestinal or perianal fistulas. In contrast, in ulcerative colitis, the inflammation is continuous and limited to rectal and colonic mucosal layers; fistulas and granulomas are not observed. Both diseases include extraintestinal inflammation of the skin, eyes, or joints. {ECO:0000269|PubMed:11385576, ECO:0000269|PubMed:15024686, ECO:0000269|PubMed:16485124, ECO:0000269|PubMed:24790089, ECO:0000269|PubMed:24960071, ECO:0000269|PubMed:27812135}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.; DISEASE: Yao syndrome (YAOS) [MIM:617321]: An autoinflammatory disease characterized by periodic fever, dermatitis, polyarthritis, leg swelling, and gastrointestinal and sicca-like symptoms. YAOS is a complex disease with multifactorial inheritance. {ECO:0000269|PubMed:21914217, ECO:0000269|PubMed:26070941}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.693
Intolerance Scores
- LoFtool
- 0.863
- RVIS EVS
- 0.57
- RVIS percentile EVS
- 82.09
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- N
- Indispensability score
- 0.447
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |