NOD2

nucleotide binding oligomerization domain containing 2, the group of Caspase recruitment domain containing|NLR family

Basic information

Region (hg38): 16:50693588-50733077

Previous symbols: [ "IBD1", "CARD15" ]

Links

ENSG00000167207 ∙ NCBI:64127 ∙ OMIM:605956 ∙ HGNC:5331 ∙ Uniprot:Q9HC29 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• Blau syndrome (Strong), mode of inheritance: AD
• Blau syndrome (Definitive), mode of inheritance: AD
• Blau syndrome (Supportive), mode of inheritance: AD
• Blau syndrome (Strong), mode of inheritance: AD
• Blau syndrome (Strong), mode of inheritance: AD
• inflammatory bowel disease 1 (Limited), mode of inheritance: Unknown
• Blau syndrome (Definitive), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Blau syndrome; Yao syndrome; Sarcoidosis, early-onset	AD/AR	Allergy/Immunology/Infectious	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	Allergy/Immunology/Infectious; Dermatologic; Musculoskeletal; Ophthalmologic; Pulmonary	4056967; 3993660; 8394645; 8882056; 9508240; 11385576; 11528384; 12879366 ; 15086578; 15459013; 17698784; 17804789 ; 21788900; 21914217; 21951874; 22147245; 22509093; 22821420; 22859352; 23102769; 23124805; 26070941; 33394828
Variants may also be related to susceptibility to Yao syndrome

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the NOD2 gene.

• Blau syndrome (7 variants)
• Regional enteritis;Blau syndrome (5 variants)
• not provided (2 variants)
• Inflammatory bowel disease 1 (1 variants)
• Blau syndrome;Regional enteritis (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the NOD2 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			9	194	9	212
missense	7	4	418	42	3	474
nonsense	1		22			23
start loss			4			4
frameshift	1		20			21
inframe indel			4			4
splice donor/acceptor (+/-2bp)			7			7
splice region			11	8	1	20
non coding			22	48	20	90
Total	9	4	506	284	32

Variants in NOD2

This is a list of pathogenic ClinVar variants found in the NOD2 region.

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

Position	Type	Phenotype	Significance	ClinVar
16-50696420-A-G			not provided (-)
16-50696869-C-A			not provided (-)
16-50696956-G-T		Blau syndrome	Uncertain significance (Feb 13, 2023)
16-50697082-T-C			not provided (-)
16-50697100-C-T			not provided (-)
16-50697147-AT-A		Crohn disease • Blau syndrome	Likely benign (Jun 14, 2016)
16-50697153-G-C			not provided (-)
16-50697185-G-A		Blau syndrome • Inflammatory bowel disease 1 • not specified	Benign (Nov 12, 2023)
16-50697186-T-C		Blau syndrome • Inflammatory bowel disease 1	Benign/Likely benign (Jan 12, 2018)
16-50697191-C-T		Blau syndrome • Inflammatory bowel disease 1	Uncertain significance (Jan 13, 2018)
16-50697230-C-T		Blau syndrome • Inflammatory bowel disease 1	Benign/Likely benign (Jan 12, 2018)
16-50697244-A-G		Autoinflammatory syndrome	Uncertain significance (Dec 12, 2016)
16-50697245-T-C		Blau syndrome;Regional enteritis	Uncertain significance (Aug 26, 2021)
16-50697246-G-A		Autoinflammatory syndrome	Uncertain significance (Apr 01, 2019)
16-50697250-G-C		Blau syndrome;Regional enteritis	Uncertain significance (Feb 01, 2023)
16-50697256-G-C		Blau syndrome;Regional enteritis	Likely benign (Oct 07, 2022)
16-50697256-G-T		Inborn genetic diseases	Uncertain significance (Dec 13, 2021)
16-50697262-T-G		Inborn genetic diseases	Uncertain significance (Jul 06, 2021)
16-50697264-AG-A		Regional enteritis;Blau syndrome	Uncertain significance (Oct 12, 2023)
16-50697265-G-T		Regional enteritis;Blau syndrome	Uncertain significance (Apr 07, 2023)
16-50697269-C-T		Regional enteritis;Blau syndrome	Uncertain significance (Dec 23, 2023)
16-50697273-C-T		Regional enteritis;Blau syndrome	Likely benign (Apr 25, 2022)
16-50697274-G-A		Regional enteritis;Blau syndrome • Inborn genetic diseases	Uncertain significance (Apr 08, 2023)
16-50697275-A-T		Regional enteritis;Blau syndrome	Uncertain significance (Feb 18, 2023)
16-50697279-G-A		Blau syndrome;Regional enteritis	Likely benign (Sep 02, 2022)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
NOD2	protein_coding	protein_coding	ENST00000300589	12	39475

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.98e-30	0.0000210	121887	110	3751	125748	0.0155

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	-0.453	616	585	1.05	0.0000368	6705
Missense in 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

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.0136	0.0136
Ashkenazi Jewish	0.0346	0.0336
East Asian	0.000218	0.000217
Finnish	0.0158	0.0156
European (Non-Finnish)	0.0238	0.0233
Middle Eastern	0.000218	0.000217
South Asian	0.00219	0.00219
Other	0.0168	0.0168

dbNSFP

Source: dbNSFP

• 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.
• Pathway: 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);Nucleotide-binding Oligomerization Domain (NOD) pathway;Toll Like Receptor 7/8 (TLR7/8) Cascade;Interleukin-17 signaling;Signaling by Interleukins;Cytokine Signaling in Immune system;Toll Like Receptor 9 (TLR9) Cascade;MyD88 cascade initiated on plasma membrane;Toll Like Receptor 10 (TLR10) Cascade;Toll Like Receptor 3 (TLR3) Cascade;Toll Like Receptor 5 (TLR5) Cascade;Toll-Like Receptors Cascades;NOD1/2 Signaling Pathway;Nucleotide-binding domain, leucine rich repeat containing receptor (NLR) signaling pathways;Post-translational protein modification;Metabolism of proteins;Interleukin-1 signaling;Innate Immune System;Immune System;TAK1 activates NFkB by phosphorylation and activation of IKKs complex;JNK (c-Jun kinases) phosphorylation and activation mediated by activated human TAK1;activated TAK1 mediates p38 MAPK activation;MAP kinase activation;TRAF6 mediated induction of NFkB and MAP kinases upon TLR7/8 or 9 activation;MyD88 dependent cascade initiated on endosome;Ovarian tumor domain proteases;Deubiquitination;TRIF(TICAM1)-mediated TLR4 signaling ;MyD88-independent TLR4 cascade ;Toll Like Receptor 4 (TLR4) Cascade;Canonical NF-kappaB pathway;MyD88:Mal cascade initiated on plasma membrane;Toll Like Receptor TLR1:TLR2 Cascade;Toll Like Receptor TLR6:TLR2 Cascade;Toll Like Receptor 2 (TLR2) Cascade;Interleukin-1 family signaling (Consensus)

Recessive Scores

• pRec: 0.693

Intolerance Scores

• loftool: 0.863
• rvis_EVS: 0.57
• rvis_percentile_EVS: 82.09

Haploinsufficiency Scores

• pHI: 0.135
• hipred: N
• hipred_score: 0.394
• ghis: 0.473

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: N
• gene_indispensability_score: 0.447

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Nod2
• Phenotype: digestive/alimentary phenotype; skeleton phenotype; immune system phenotype; growth/size/body region phenotype; hematopoietic system 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); homeostasis/metabolism phenotype; cellular phenotype

Gene ontology

• 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;positive regulation of type 2 immune response;defense response;JNK cascade;response to nutrient;detection of biotic stimulus;detection of bacterium;maintenance of gastrointestinal epithelium;response to muramyl dipeptide;detection of muramyl dipeptide;positive regulation of interleukin-1 beta production;positive regulation of interleukin-10 production;positive regulation of interleukin-17 production;positive regulation of interleukin-6 production;positive regulation of interleukin-8 production;positive regulation of tumor necrosis factor production;positive regulation of stress-activated MAPK cascade;intracellular signal transduction;defense response to bacterium;positive regulation of I-kappaB kinase/NF-kappaB signaling;positive regulation of MAP kinase activity;positive regulation of phosphatidylinositol 3-kinase activity;innate immune response;positive regulation of Notch signaling pathway;positive regulation of transcription by RNA polymerase II;positive regulation of JNK cascade;positive regulation of gamma-delta T cell activation;positive regulation of epithelial cell proliferation;positive regulation of interleukin-1 beta secretion;regulation of inflammatory response;positive regulation of B cell activation;positive regulation of NF-kappaB transcription factor activity;protein complex oligomerization;positive regulation of oxidoreductase activity;positive regulation of nitric-oxide synthase biosynthetic process;positive regulation of prostaglandin-endoperoxide synthase activity;positive regulation of ERK1 and ERK2 cascade;nucleotide-binding oligomerization domain containing signaling pathway;nucleotide-binding oligomerization domain containing 2 signaling pathway;interleukin-1-mediated signaling pathway;cellular response to lipopolysaccharide;cellular response to peptidoglycan;cellular response to muramyl dipeptide;cellular response to organic cyclic compound;positive regulation of cytokine production involved in inflammatory response;positive regulation of NIK/NF-kappaB signaling;positive regulation of protein K63-linked ubiquitination;negative regulation of macrophage apoptotic process;positive regulation of prostaglandin-E synthase activity
• Cellular component: cytoplasm;mitochondrion;Golgi apparatus;cytosol;cytoskeleton;plasma membrane;cell surface;basolateral plasma membrane;vesicle;protein-containing complex
• Molecular function: actin binding;protein binding;ATP binding;enzyme binding;protein kinase binding;Hsp70 protein binding;muramyl dipeptide binding;peptidoglycan binding;protein-containing complex binding;CARD domain binding;Hsp90 protein binding