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rs2066844

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

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. 11/19 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

Scores

1
11

Clinical Significance

Conflicting classifications of pathogenicity; association criteria provided, conflicting classifications U:3B:4O:4

Conservation

PhyloP100: 0.742
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]

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ACMG classification

Classification made for transcript

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
NOD2NM_001370466.1 linkuse as main transcriptc.2023C>T p.Arg675Trp missense_variant 4/12 ENST00000647318.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
NOD2ENST00000647318.2 linkuse as main transcriptc.2023C>T p.Arg675Trp missense_variant 4/12 NM_001370466.1 P1Q9HC29-2
NOD2ENST00000300589.6 linkuse as main transcriptc.2104C>T p.Arg702Trp missense_variant 4/121 Q9HC29-1
NOD2ENST00000641284.2 linkuse as main transcriptc.2023C>T p.Arg675Trp missense_variant, NMD_transcript_variant 4/6
NOD2ENST00000646677.2 linkuse as main transcriptc.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
show subpopulations
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
show subpopulations
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
show subpopulations
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
show subpopulations
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:3Benign:4Other:4
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not specified Uncertain:1Benign:1
Benign, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineMar 29, 2016Variant 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 -
Uncertain significance, criteria provided, single submitterclinical testingGenomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of PhiladelphiaApr 17, 2015- -
Yao syndrome Uncertain:1Other:1
risk factor, no assertion criteria providedliterature onlyOMIMJul 01, 2002- -
Uncertain significance, criteria provided, single submitterclinical testingUndiagnosed Diseases Network, NIHAug 18, 2020- -
Inflammatory bowel disease 1 Benign:1Other:1
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaApr 27, 2017This 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. -
risk factor, no assertion criteria providedliterature onlyOMIMJul 01, 2002- -
Autoinflammatory syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGenome Diagnostics Laboratory, The Hospital for Sick ChildrenApr 19, 2022- -
not provided Benign:1
Benign, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesNov 29, 2023- -
Blau syndrome Benign:1
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaApr 27, 2017This 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 submitterclinical testingInvitaeJan 31, 2024This 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 providedphenotyping onlyGenomeConnect - 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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs2066844; hg19: chr16-50745926; API