rs104895431
Variant summary
Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2
The NM_001370466.1(NOD2):c.1211C>T(p.Ser404Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00136 in 1,614,046 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S404S) 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 -13 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NOD2 | NM_001370466.1 | c.1211C>T | p.Ser404Leu | missense_variant | 4/12 | ENST00000647318.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NOD2 | ENST00000647318.2 | c.1211C>T | p.Ser404Leu | missense_variant | 4/12 | NM_001370466.1 | P1 | ||
NOD2 | ENST00000300589.6 | c.1292C>T | p.Ser431Leu | missense_variant | 4/12 | 1 | |||
NOD2 | ENST00000641284.2 | c.1211C>T | p.Ser404Leu | missense_variant, NMD_transcript_variant | 4/6 | ||||
NOD2 | ENST00000646677.2 | c.1211C>T | p.Ser404Leu | missense_variant, NMD_transcript_variant | 4/13 |
Frequencies
GnomAD3 genomes ? AF: 0.000979 AC: 149AN: 152228Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000965 AC: 242AN: 250764Hom.: 2 AF XY: 0.000943 AC XY: 128AN XY: 135668
GnomAD4 exome AF: 0.00140 AC: 2047AN: 1461700Hom.: 9 Cov.: 40 AF XY: 0.00139 AC XY: 1013AN XY: 727172
GnomAD4 genome ? AF: 0.000978 AC: 149AN: 152346Hom.: 0 Cov.: 33 AF XY: 0.000819 AC XY: 61AN XY: 74492
ClinVar
Submissions by phenotype
not provided Benign:2
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2024 | NOD2: BP4, BS1 - |
Likely benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Nov 01, 2023 | - - |
Blau syndrome Benign:1Other:1
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Mar 06, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
not provided, no classification provided | literature only | Unité médicale des maladies autoinflammatoires, CHRU Montpellier | - | - - |
Inflammatory bowel disease 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Mar 06, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
NOD2-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Dec 22, 2023 | The NOD2 c.1292C>T variant is predicted to result in the amino acid substitution p.Ser431Leu. This variant has been reported in individuals with inflammatory bowel disease or Crohn’s disease (Lesage et al. 2002. PubMed ID: 11875755; Rivas et al. 2011. PubMed ID: 21983784). Of note, this variant was also reported in patients with childhood onset inflammatory bowel disease (pIBD) (Andreoletti et al. 2017. PubMed ID: 28422189; Chen et al. 2018. PubMed ID: 30166421). This variant was also reported in the presence of additional NOD2 variants [c.2377G>A (p.Val793Met) and c.2798+158C>T] in at least two patients with NOD2-associated autoinflammatory disease (Yao et al. 2015. PubMed ID: 26070941). This variant was also reported in one individual in a study of patients with inherited retinal and optical nerve disorders (Table S12, Diñeiro et al. 2020. PubMed ID: 32483926) and was identified in an individual with orofacial granulomatosis (Mentzer et al. 2016. PubMed ID: 27306066). Functional studies showed that this variant altered NOD2 protein localization and function (Rivas et al. 2011. PubMed ID: 21983784). This variant is reported in 0.16% of alleles in individuals of European (Non-Finnish) descent in gnomAD, including two homozygous individuals and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from uncertain significance to likely benign to benign (https://www.ncbi.nlm.nih.gov/clinvar/variation/97826/). However, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Regional enteritis;C5201146:Blau syndrome Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 27, 2024 | - - |
Autoinflammatory syndrome Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Jun 01, 2020 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at