rs2066844

Variant names:

• chr16-50712015-C-T
• rs2066844
• NM_001370466.1:c.2023C>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.2023C>T​(p.Arg675Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0385 in 1,613,122 control chromosomes in the GnomAD database, including 1,697 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict 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. R675Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.028 (111 hom., cov: 33)
  • Exomes 𝑓: 0.040 (1586 hom.)
• Consequence: NOD2 NM_001370466.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity; association criteria provided, conflicting classifications U:3 B:6 O:5
• Conservation: PhyloP100: 0.742
• Publications: 817 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=0.0020624995).
• BP6: Variant 16-50712015-C-T is Benign according to our data. Variant chr16-50712015-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity|association. ClinVar VariationId is 4693.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0284 (4330/152352) while in subpopulation NFE AF = 0.0451 (3065/68026). AF 95% confidence interval is 0.0437. There are 111 homozygotes in GnomAd4. There are 1998 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 4330 AD,Unknown gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOD2	NM_001370466.1	c.2023C>T	p.Arg675Trp	missense_variant	Exon 4 of 12	ENST00000647318.2	NP_001357395.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOD2	ENST00000647318.2	c.2023C>T	p.Arg675Trp	missense_variant	Exon 4 of 12		NM_001370466.1	ENSP00000495993.1

Frequencies

GnomAD3 genomes AF: 0.0284 AC: 4330 AN: 152234 Hom.: 111 Cov.: 33

Gnomad AFR AF: 0.00854

Gnomad AMI AF: 0.159

Gnomad AMR AF: 0.0322

Gnomad ASJ AF: 0.0156

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.0144

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0451

Gnomad OTH AF: 0.0301

GnomAD2 exomes AF: 0.0261 AC: 6476 AN: 248574 AF XY: 0.0262

Gnomad AFR exome AF: 0.00699

Gnomad AMR exome AF: 0.0202

Gnomad ASJ exome AF: 0.0223

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0187

Gnomad NFE exome AF: 0.0433

Gnomad OTH exome AF: 0.0304

GnomAD4 exome AF: 0.0396 AC: 57781 AN: 1460770 Hom.: 1586 Cov.: 34 AF XY: 0.0383 AC XY: 27842 AN XY: 726726

African (AFR) AF: 0.00654 AC: 219 AN: 33478

American (AMR) AF: 0.0216 AC: 967 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.0208 AC: 542 AN: 26110

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39700

South Asian (SAS) AF: 0.000359 AC: 31 AN: 86234

European-Finnish (FIN) AF: 0.0182 AC: 957 AN: 52572

Middle Eastern (MID) AF: 0.00434 AC: 25 AN: 5762

European-Non Finnish (NFE) AF: 0.0478 AC: 53173 AN: 1111848

Other (OTH) AF: 0.0309 AC: 1863 AN: 60362

GnomAD4 genome AF: 0.0284 AC: 4330 AN: 152352 Hom.: 111 Cov.: 33 AF XY: 0.0268 AC XY: 1998 AN XY: 74496

African (AFR) AF: 0.00851 AC: 354 AN: 41590

American (AMR) AF: 0.0321 AC: 492 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0156 AC: 54 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5188

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4832

European-Finnish (FIN) AF: 0.0144 AC: 153 AN: 10616

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0451 AC: 3065 AN: 68026

Other (OTH) AF: 0.0298 AC: 63 AN: 2116

Alfa AF: 0.0411 Hom.: 346

Bravo AF: 0.0299

TwinsUK AF: 0.0456 AC: 169

ALSPAC AF: 0.0485 AC: 187

ESP6500AA AF: 0.00820 AC: 36

ESP6500EA AF: 0.0435 AC: 374

ExAC AF: 0.0226 AC: 2743

EpiCase AF: 0.0470

EpiControl AF: 0.0418

ClinVar

Significance: Conflicting classifications of pathogenicity; association

Submissions summary: Uncertain:3 Benign:6 Other:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:1

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

Apr 17, 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

- -

Yao syndrome Uncertain:1 Other:1

Jul 01, 2002

OMIM

Significance: risk factor

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Aug 18, 2020

Undiagnosed Diseases Network, NIH

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

Oct 29, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 05, 2024

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

See Variant Classification Assertion Criteria. -

Inflammatory bowel disease 1 Benign:1 Other:1

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. -

Jul 01, 2002

OMIM

Significance: risk factor

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Blau syndrome Benign:1 Other:1

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. -

-

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant classified as Increased Risk Allele and reported on 07-07-2022 by Invitae. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Autoinflammatory syndrome Uncertain:1

Apr 19, 2022

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Jan 31, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: research

- -

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 arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 702 of the NOD2 protein (p.Arg702Trp). This variant is present in population databases (rs2066844, gnomAD 4%), 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: 11385576, 21548950, 18489434, 21274544, 15770725, 15024686, 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 = 2.2, 95% CI 2.0-2.5). 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 referred to as R675W and SNP8 in the literature. ClinVar contains an entry for this variant (Variation ID: 4693). 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) indicates that this missense variant is not expected to disrupt NOD2 protein function with a negative predictive value of 95%. Experimental studies have shown that this missense change results in decreased NFkB activity and decreased response to lipopolysaccharide, muramyl dipeptide, and peptidoglycan compared to wildtype protein (PMID: 12512038, 15198989, 18240302, 22684479). In summary, this is a frequently observed variant that is associated with approximately a 2.2-fold increased risk of Crohn's disease in population studies. Therefore, it has been classified as an Increased Risk Allele. -

Crohn disease Other:1

-

GenomeConnect - Invitae Patient Insights Network

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant reported in multiple Invitae PIN participants. Variant interpreted as an increased risk allele and reported most recently on 6/29/2020 Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	23
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.33	.;T
Eigen	Benign	0.12
Eigen_PC	Benign	-0.0062
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.85	D;D
MetaRNN	Benign	0.0021	T;T
MetaSVM	Benign	-0.86	T
MutationAssessor	Uncertain	2.6	.;M
PhyloP100		0.74
PrimateAI	Benign	0.29	T
PROVEAN	Uncertain	-3.3	.;D
REVEL	Benign	0.24
Sift	Uncertain	0.0010	.;D
Sift4G	Uncertain	0.0060	.;D
Polyphen		1.0	D;D
Vest4		0.046
MPC		0.10
ClinPred		0.025	T
GERP RS		3.7
PromoterAI		0.037	Neutral
Varity_R		0.18
gMVP		0.48
Mutation Taster		=97/3	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: rs2066844; hg19: chr16-50745926; COSMIC: COSV107363615; COSMIC: COSV107363615;