rs2066845

chr16-50722629-G-Cchr16-50722629-G-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.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:4 O:3
• Conservation: PhyloP100: 4.50

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=0.010364234).
• 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 9 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NOD2	NM_001370466.1	c.2641G>C	p.Gly881Arg	missense_variant	8/12	ENST00000647318.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NOD2	ENST00000647318.2	c.2641G>C	p.Gly881Arg	missense_variant	8/12		NM_001370466.1	P1

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

GnomAD3 exomes AF: 0.0113 AC: 2837 AN: 251458 Hom.: 43 AF XY: 0.0118 AC XY: 1606 AN XY: 135898

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 SAS exome AF: 0.00800

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

Gnomad4 AFR exome AF: 0.00227

Gnomad4 AMR exome AF: 0.00854

Gnomad4 ASJ exome AF: 0.0423

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00907

Gnomad4 FIN exome AF: 0.00292

Gnomad4 NFE exome AF: 0.0141

Gnomad4 OTH exome AF: 0.0135

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

Gnomad4 AFR AF: 0.00274

Gnomad4 AMR AF: 0.0138

Gnomad4 ASJ AF: 0.0432

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00621

Gnomad4 FIN AF: 0.00254

Gnomad4 NFE AF: 0.0147

Gnomad4 OTH AF: 0.0161

Alfa AF: 0.0142 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:4 Other:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter	clinical testing	Al Jalila Children's Genomics Center, Al Jalila Childrens Speciality Hospital	Dec 10, 2020	- -
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. -

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 22, 2023	- -

Blau syndrome Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
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. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Nov 11, 2015

- -

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

Uncertain significance, criteria provided, single submitter

clinical testing

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

Apr 15, 2021

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. -

Autoinflammatory syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Feb 05, 2022

- -

Yao syndrome Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Jul 01, 2002

- -

Regional enteritis;C5201146:Blau syndrome Other:1

association, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

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). 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 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
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
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.64	T
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

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