rs2066844

chr16-50712015-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong 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. 12/20 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:4 O:4
• Conservation: PhyloP100: 0.742

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0020624995).
• 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 male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 111 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NOD2	NM_001370466.1	c.2023C>T	p.Arg675Trp	missense_variant	4/12	ENST00000647318.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NOD2	ENST00000647318.2	c.2023C>T	p.Arg675Trp	missense_variant	4/12		NM_001370466.1	P1
NOD2	ENST00000300589.6	c.2104C>T	p.Arg702Trp	missense_variant	4/12	1
NOD2	ENST00000641284.2	c.2023C>T	p.Arg675Trp	missense_variant, NMD_transcript_variant	4/6
NOD2	ENST00000646677.2	c.2023C>T	p.Arg675Trp	missense_variant, NMD_transcript_variant	4/13

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

GnomAD3 exomes AF: 0.0261 AC: 6476 AN: 248574 Hom.: 168 AF XY: 0.0262 AC XY: 3538 AN XY: 134846

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 SAS exome AF: 0.000392

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

Gnomad4 AFR exome AF: 0.00654

Gnomad4 AMR exome AF: 0.0216

Gnomad4 ASJ exome AF: 0.0208

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.000359

Gnomad4 FIN exome AF: 0.0182

Gnomad4 NFE exome AF: 0.0478

Gnomad4 OTH exome AF: 0.0309

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

Gnomad4 AFR AF: 0.00851

Gnomad4 AMR AF: 0.0321

Gnomad4 ASJ AF: 0.0156

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.0144

Gnomad4 NFE AF: 0.0451

Gnomad4 OTH AF: 0.0298

Alfa AF: 0.0428 Hom.: 268

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:4 Other:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Apr 17, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	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 -

Yao syndrome Uncertain:1 Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	Undiagnosed Diseases Network, NIH	Aug 18, 2020	- -
risk factor, no assertion criteria provided	literature only	OMIM	Jul 01, 2002	- -

Inflammatory bowel disease 1 Benign:1 Other:1

risk factor, no assertion criteria provided	literature only	OMIM	Jul 01, 2002	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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. -

Autoinflammatory syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Apr 19, 2022

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Nov 29, 2023

- -

Blau syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

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. -

Regional enteritis;C5201146:Blau syndrome Other:1

association, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

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). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae 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

not provided, no classification provided

phenotyping only

GenomeConnect - Invitae Patient Insights Network

-

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
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
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.29	T
Polyphen		1.0	D;D
Vest4		0.046
MPC		0.10
ClinPred		0.025	T
GERP RS		3.7
Varity_R		0.18
gMVP		0.48

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

Publications

LitVar

Other links and lift over

dbSNP: rs2066844; hg19: chr16-50745926;