rs2066845

Variant names:

• chr16-50722629-G-C
• rs2066845
• NM_001370466.1:c.2641G>C

Your query was ambiguous. Multiple possible variants found:

• chr16-50722629-G-C
• chr16-50722629-G-T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001370466.1(NOD2):​c.2641G>C​(p.Gly881Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0129 in 1,614,104 control chromosomes in the GnomAD database, including 245 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity,association (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G881C) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.010 (9 hom., cov: 32)
  • Exomes 𝑓: 0.013 (236 hom.)
• Consequence: NOD2 NM_001370466.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity; association criteria provided, conflicting classifications U:5 B:5 O:3
• Conservation: PhyloP100: 4.50
• Publications: 741 publications found

Genes affected

NOD2 (HGNC:5331): (nucleotide binding oligomerization domain containing 2) 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]

NOD2 Gene-Disease associations (from GenCC):

• Blau syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet, Genomics England PanelApp, G2P, Illumina, Labcorp Genetics (formerly Invitae)
• inflammatory bowel disease 1

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010364234).
• BP6: Variant 16-50722629-G-C is Benign according to our data. Variant chr16-50722629-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity|association. ClinVar VariationId is 4692.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0103 (1573/152288) while in subpopulation NFE AF = 0.0147 (997/68010). AF 95% confidence interval is 0.0139. There are 9 homozygotes in GnomAd4. There are 745 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1573 AD,Unknown gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOD2	NM_001370466.1	c.2641G>C	p.Gly881Arg	missense_variant	Exon 8 of 12	ENST00000647318.2	NP_001357395.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOD2	ENST00000647318.2	c.2641G>C	p.Gly881Arg	missense_variant	Exon 8 of 12		NM_001370466.1	ENSP00000495993.1

Frequencies

GnomAD3 genomes AF: 0.0103 AC: 1571 AN: 152170 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.00275

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0139

Gnomad ASJ AF: 0.0432

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00579

Gnomad FIN AF: 0.00254

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0147

Gnomad OTH AF: 0.0163

GnomAD2 exomes AF: 0.0113 AC: 2837 AN: 251458 AF XY: 0.0118

Gnomad AFR exome AF: 0.00160

Gnomad AMR exome AF: 0.00890

Gnomad ASJ exome AF: 0.0463

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00309

Gnomad NFE exome AF: 0.0143

Gnomad OTH exome AF: 0.0165

GnomAD4 exome AF: 0.0131 AC: 19221 AN: 1461816 Hom.: 236 Cov.: 31 AF XY: 0.0133 AC XY: 9644 AN XY: 727210

African (AFR) AF: 0.00227 AC: 76 AN: 33480

American (AMR) AF: 0.00854 AC: 382 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0423 AC: 1105 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.00907 AC: 782 AN: 86256

European-Finnish (FIN) AF: 0.00292 AC: 156 AN: 53420

Middle Eastern (MID) AF: 0.0380 AC: 219 AN: 5768

European-Non Finnish (NFE) AF: 0.0141 AC: 15684 AN: 1111936

Other (OTH) AF: 0.0135 AC: 815 AN: 60396

GnomAD4 genome AF: 0.0103 AC: 1573 AN: 152288 Hom.: 9 Cov.: 32 AF XY: 0.0100 AC XY: 745 AN XY: 74466

African (AFR) AF: 0.00274 AC: 114 AN: 41556

American (AMR) AF: 0.0138 AC: 212 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0432 AC: 150 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00621 AC: 30 AN: 4830

European-Finnish (FIN) AF: 0.00254 AC: 27 AN: 10622

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0147 AC: 997 AN: 68010

Other (OTH) AF: 0.0161 AC: 34 AN: 2112

Alfa AF: 0.0127 Hom.: 24

Bravo AF: 0.0101

TwinsUK AF: 0.0148 AC: 55

ALSPAC AF: 0.0117 AC: 45

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.0145 AC: 125

ExAC AF: 0.00992 AC: 1204

Asia WGS AF: 0.00433 AC: 15 AN: 3478

EpiCase AF: 0.0164

EpiControl AF: 0.0151

ClinVar

Significance: Conflicting classifications of pathogenicity; association

Submissions summary: Uncertain:5 Benign:5 Other:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Inflammatory bowel disease 1 Uncertain:1 Benign:1 Other:1

Jul 01, 2002

OMIM

Significance: risk factor

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Dec 10, 2020

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Blau syndrome Uncertain:1 Benign:1

May 28, 2019

Mendelics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

not provided Benign:2

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NOD2: BS1, BS2 -

Nov 22, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Uncertain:1

Nov 11, 2015

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Psoriatic arthritis, susceptibility to;C4310620:Yao syndrome;C5201146:Blau syndrome;CN260071:Inflammatory bowel disease 1 Uncertain:1

-

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NOD2 NM_022162.2 exon 8 p.Gly908Arg (c.2722G>C):This variant has been reported in the literature in numerous individuals with a variety of phenotypes, most often in the context of immunological related presentations such as Crohn's disease or Irritable Bowel Disease (IBD) (Hugot 2001 PMID:11385576, Cuthbert 2002 PMID:11910337, Bonen 2003 PMID:12512038, Kabesch 2003 PMID:12704363, Girardelli 2018 PMID:29248579, Hui 2018 PMID:29321258, Gonzalez-Mancera 2020 PMID:32654169). In a large meta analysis study (PMID: 19713276), Individuals carrying this variant had an increased overall risk of Crohn's disease (OR = 2.6, 95% CI 2.2-2.9). However, this variant is present in several control individuals in the literature and is present in 1.4% (997/68018) of European alleles, including 5 homozygotes in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/16-50722629-G-C?dataset=gnomad_r3). This variant is present in ClinVar (Variation ID:4692) with classifications ranging from Variant of Uncertain Significance to Likely Benign as well as at least 1 entry as a Risk Allele. Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In vitro functional studies predict that this variant will impact the protein (Bonen 2003 PMID:12512038). However, these studies may not accurately represent in vivo biological function. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain but given the available data, the classification of this variant is likely most appropriate as a risk allele. -

Yao syndrome;C5201146:Blau syndrome;CN260071:Inflammatory bowel disease 1 Uncertain:1

Jul 26, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

- -

Autoinflammatory syndrome Benign:1

Feb 05, 2022

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Yao syndrome Other:1

Jul 01, 2002

OMIM

Significance: risk factor

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Regional enteritis;C5201146:Blau syndrome Other:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: association

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 908 of the NOD2 protein (p.Gly908Arg). This variant is present in population databases (rs2066845, gnomAD 5%), including at least one homozygous and/or hemizygous individual. Numerous population-based case-control studies have shown that this variant confers an elevated risk of Crohn's disease (PMID: 21548950, 15024686, 18489434, 15190267, 15571588). In a large meta-analysis involving 75 case-control studies with 18,727 cases and 17,102 controls (PMID: 19713276), individuals carrying this variant had an increased overall risk of Crohn's disease (OR = 2.6, 95% CI 2.2-2.9). When all three NOD2 genotypes were combined (p.Arg702Trp, p.Gly908Arg, and p.Leu1007Profs*2), the odds ratios for Crohn's disease were 2.4 (95% CI, 2.0-2.8) for simple heterozygotes, 9.0 (95% CI 6.0-13.5) for compound heterozygotes, and 6.7 (95% CI 4.1-10.9) for homozygotes, compared with noncarriers. This variant is also known as G881R in the literature. ClinVar contains an entry for this variant (Variation ID: 4692). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on NOD2 protein function. Experimental studies have shown that this missense change results in decreased NFkB activity and decreased response to lipopolysaccharide and peptidoglycan compared to wildtype protein (PMID: 12512038, 15198989). In summary, this is a frequently observed variant that is associated with approximately a 2.6-fold increased risk of Crohn's disease in population studies. Therefore, it has been classified as an Increased Risk Allele. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Benign	-0.076	T
BayesDel_noAF	Pathogenic	0.14
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.25	.;T
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.77	T;T
MetaRNN	Benign	0.010	T;T
MetaSVM	Benign	-0.70	T
MutationAssessor	Benign	0.98	.;L
PhyloP100		4.5
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-5.8	.;D
REVEL	Uncertain	0.34
Sift	Pathogenic	0.0	.;D
Sift4G	Uncertain	0.0080	.;D
Polyphen		1.0	D;D
Vest4		0.75
MPC		0.54
ClinPred		0.029	T
GERP RS		5.9
Varity_R		0.83
gMVP		0.56
Mutation Taster		=77/23	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2066845; hg19: chr16-50756540; COSMIC: COSV56054563; COSMIC: COSV56054563;