rs562225614
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PP3_Strong
The NM_001370466.1(NOD2):c.1196G>A(p.Arg399His) variant causes a missense change. The variant allele was found at a frequency of 0.0000564 in 1,614,058 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R399C) has been classified as Uncertain significance.
Frequency
Consequence
NM_001370466.1 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
NOD2 | NM_001370466.1 | c.1196G>A | p.Arg399His | missense_variant | Exon 4 of 12 | ENST00000647318.2 | NP_001357395.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000460 AC: 7AN: 152194Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000877 AC: 22AN: 250964Hom.: 0 AF XY: 0.0000589 AC XY: 8AN XY: 135730
GnomAD4 exome AF: 0.0000581 AC: 85AN: 1461746Hom.: 1 Cov.: 39 AF XY: 0.0000468 AC XY: 34AN XY: 727180
GnomAD4 genome AF: 0.0000394 AC: 6AN: 152312Hom.: 0 Cov.: 33 AF XY: 0.0000671 AC XY: 5AN XY: 74474
ClinVar
Submissions by phenotype
not provided Uncertain:1
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29697845, 32085886, 34440800, 32677123) -
Regional enteritis;C5201146:Blau syndrome Uncertain:1
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 426 of the NOD2 protein (p.Arg426His). This variant is present in population databases (rs562225614, gnomAD 0.02%). This missense change has been observed in individual(s) with early-onset inflammatory bowel disease (PMID: 29697845). ClinVar contains an entry for this variant (Variation ID: 531600). 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) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on NOD2 protein function. Experimental studies have shown that this missense change affects NOD2 function (PMID: 29697845). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at