rs104895467

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001370466.1(NOD2):c.2474A>G(p.Asn825Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00071 in 1,614,080 control chromosomes in the GnomAD database, including 4 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).

Frequency

Genomes: 𝑓 0.00076 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00070 ( 4 hom. )

Consequence

NOD2
NM_001370466.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity; association criteria provided, conflicting classifications U:2B:7O:2

Conservation

PhyloP100: 6.17

Publications

32 publications found

Variant links:

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)

NOD2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (MetaRNN=0.009353697).

BP6

Variant 16-50716899-A-G is Benign according to our data. Variant chr16-50716899-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity|association. ClinVar VariationId is 97856.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000761 (116/152366) while in subpopulation AMR AF = 0.000849 (13/15304). AF 95% confidence interval is 0.00056. There are 0 homozygotes in GnomAd4. There are 51 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 116 AD,Unknown gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOD2	NM_001370466.1 link	c.2474A>G	p.Asn825Ser	missense_variant	Exon 6 of 12	ENST00000647318.2	NP_001357395.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOD2	ENST00000647318.2 link	c.2474A>G	p.Asn825Ser	missense_variant	Exon 6 of 12		NM_001370466.1	ENSP00000495993.1		Q9HC29-2

Frequencies

GnomAD3 genomes

AF:

0.000762

AC:

116

AN:

152248

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000964

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000851

Gnomad ASJ

AF:

0.0130

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000720

Gnomad OTH

AF:

0.00143

GnomAD2 exomes

AF:

0.00117

AC:

295

AN:

251494

AF XY:

0.00105

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.000781

Gnomad ASJ exome

AF:

0.0161

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000835

Gnomad OTH exome

AF:

0.00147

GnomAD4 exome

AF:

0.000705

AC:

1030

AN:

1461714

Hom.:

Cov.:

AF XY:

0.000666

AC XY:

484

AN XY:

727172

show subpopulations

African (AFR)

AF:

0.000119

AC:

AN:

33478

American (AMR)

AF:

0.000805

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0156

AC:

407

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00399

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000407

AC:

453

AN:

1111858

Other (OTH)

AF:

0.00176

AC:

106

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

124

186

248

310

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

110

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000761

AC:

116

AN:

152366

Hom.:

Cov.:

AF XY:

0.000685

AC XY:

AN XY:

74504

show subpopulations

African (AFR)

AF:

0.0000962

AC:

AN:

41600

American (AMR)

AF:

0.000849

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.0130

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.000207

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000720

AC:

AN:

68032

Other (OTH)

AF:

0.00142

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00109

Hom.:

Bravo

AF:

0.000971

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00116

AC:

ExAC

AF:

0.00122

AC:

148

EpiCase

AF:

0.000709

EpiControl

AF:

0.00136

ClinVar

Significance: Conflicting classifications of pathogenicity; association

Submissions summary: Uncertain:2Benign:7Other:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:4

Mar 14, 2016

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The N852S variant in the NOD2 gene has been reported in several publications as a rare risk allele associated with Crohn disease in the Ashkenazi Jewish population (Tukel et al., (2004); King et al. (2006); Rivas et al., (2011); Zhang W et al., 2013). The NHLBI ESP Exome Sequencing Project reports N852S was observed with a frequency of 0.11% in 10/8600 alleles from individuals of European background, indicating it may be a rare (benign) variant in this population. The N852S variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret N852S in NOD2 as a variant of unknown significance. -

Aug 22, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

NOD2: BS1 -

Blau syndrome

Benign:1Other:1

Unité médicale des maladies autoinflammatoires, CHRU Montpellier

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

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. -

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

Uncertain:1

Aug 18, 2020

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

Jan 29, 2021

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inflammatory bowel disease 1

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Regional enteritis;C5201146:Blau syndrome

Other:1

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:association

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 852 of the NOD2 protein (p.Asn852Ser). This variant is present in population databases (rs104895467, gnomAD 1.6%), including at least one homozygous and/or hemizygous individual. In a large association analysis involving over 40,000 cases and controls (PMID: 21983784), individuals who carried this variant had a significantly increased risk of Crohn's disease (OR=2.47, 95% CI=1.55-3.93). ClinVar contains an entry for this variant (Variation ID: 97856). 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 affects NOD2 function (PMID: 21983784). In summary, this is a common variant that is associated with an increased risk for developing disease. For these reasons, this variant has been classified as an Increased Risk Allele. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.38

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.39

.;T

Eigen

Uncertain

0.64

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.92

D;D

M_CAP

Benign

0.062

MetaRNN

Benign

0.0094

T;T

MetaSVM

Benign

-0.59

MutationAssessor

Uncertain

2.5

.;M

PhyloP100

6.2

PrimateAI

Uncertain

0.55

PROVEAN

Uncertain

-3.0

.;D

REVEL

Benign

0.23

Sift

Uncertain

0.029

.;D

Sift4G

Uncertain

0.012

.;D

Polyphen

1.0

.;D

Vest4

0.63

MVP

0.92

MPC

0.43

ClinPred

0.072

GERP RS

5.8

Varity_R

0.24

gMVP

0.14

Mutation Taster

=63/37

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over