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. 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
Consequence
NM_001370466.1 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -12 ACMG points.
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: 4330AN: 152234Hom.: 111 Cov.: 33
GnomAD3 exomes AF: 0.0261 AC: 6476AN: 248574Hom.: 168 AF XY: 0.0262 AC XY: 3538AN XY: 134846
GnomAD4 exome AF: 0.0396 AC: 57781AN: 1460770Hom.: 1586 Cov.: 34 AF XY: 0.0383 AC XY: 27842AN XY: 726726
GnomAD4 genome ? AF: 0.0284 AC: 4330AN: 152352Hom.: 111 Cov.: 33 AF XY: 0.0268 AC XY: 1998AN XY: 74496
ClinVar
Submissions by phenotype
not specified Uncertain:1Benign: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:1Other:1
risk factor, no assertion criteria provided | literature only | OMIM | Jul 01, 2002 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Undiagnosed Diseases Network, NIH | Aug 18, 2020 | - - |
Inflammatory bowel disease 1 Benign:1Other: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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at