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rs5743293

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PVS1_ModerateBS1_SupportingBS2

The NM_001370466.1(NOD2):c.2938dup(p.Leu980ProfsTer2) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0181 in 1,613,186 control chromosomes in the GnomAD database, including 607 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity,association (no stars).

Frequency

Genomes: đť‘“ 0.015 ( 30 hom., cov: 32)
Exomes đť‘“: 0.018 ( 577 hom. )

Consequence

NOD2
NM_001370466.1 frameshift

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity; association criteria provided, conflicting classifications P:3U:3B:6O:3

Conservation

PhyloP100: 1.98
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]
CYLD-AS1 (HGNC:55352): (CYLD antisense RNA 1)

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0352 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0149 (2274/152284) while in subpopulation NFE AF= 0.0231 (1570/68018). AF 95% confidence interval is 0.0221. There are 30 homozygotes in gnomad4. There are 1077 alleles in male gnomad4 subpopulation. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
BS2
High Homozygotes in GnomAd at 30 AD,AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
NOD2NM_001370466.1 linkuse as main transcriptc.2938dup p.Leu980ProfsTer2 frameshift_variant 11/12 ENST00000647318.2
CYLD-AS1NR_184279.1 linkuse as main transcriptn.498_499insG non_coding_transcript_exon_variant 5/7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
NOD2ENST00000647318.2 linkuse as main transcriptc.2938dup p.Leu980ProfsTer2 frameshift_variant 11/12 NM_001370466.1 P1Q9HC29-2
CYLD-AS1ENST00000563315.2 linkuse as main transcriptn.1099_1100insG non_coding_transcript_exon_variant 4/65

Frequencies

GnomAD3 genomes
AF:
0.0149
AC:
2274
AN:
152166
Hom.:
30
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00345
Gnomad AMI
AF:
0.0307
Gnomad AMR
AF:
0.0132
Gnomad ASJ
AF:
0.0285
Gnomad EAS
AF:
0.000193
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.0182
Gnomad MID
AF:
0.00316
Gnomad NFE
AF:
0.0231
Gnomad OTH
AF:
0.0182
GnomAD3 exomes
AF:
0.0150
AC:
3771
AN:
251370
Hom.:
108
AF XY:
0.0149
AC XY:
2028
AN XY:
135860
show subpopulations
Gnomad AFR exome
AF:
0.00289
Gnomad AMR exome
AF:
0.00845
Gnomad ASJ exome
AF:
0.0344
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00154
Gnomad FIN exome
AF:
0.0155
Gnomad NFE exome
AF:
0.0230
Gnomad OTH exome
AF:
0.0152
GnomAD4 exome
AF:
0.0185
AC:
26983
AN:
1460902
Hom.:
577
Cov.:
31
AF XY:
0.0182
AC XY:
13198
AN XY:
726788
show subpopulations
Gnomad4 AFR exome
AF:
0.00236
Gnomad4 AMR exome
AF:
0.00803
Gnomad4 ASJ exome
AF:
0.0322
Gnomad4 EAS exome
AF:
0.0000504
Gnomad4 SAS exome
AF:
0.00160
Gnomad4 FIN exome
AF:
0.0147
Gnomad4 NFE exome
AF:
0.0215
Gnomad4 OTH exome
AF:
0.0136
GnomAD4 genome
AF:
0.0149
AC:
2274
AN:
152284
Hom.:
30
Cov.:
32
AF XY:
0.0145
AC XY:
1077
AN XY:
74460
show subpopulations
Gnomad4 AFR
AF:
0.00344
Gnomad4 AMR
AF:
0.0131
Gnomad4 ASJ
AF:
0.0285
Gnomad4 EAS
AF:
0.000193
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.0182
Gnomad4 NFE
AF:
0.0231
Gnomad4 OTH
AF:
0.0180
Alfa
AF:
0.0854
Hom.:
3249
Bravo
AF:
0.0135
Asia WGS
AF:
0.00202
AC:
7
AN:
3478
EpiCase
AF:
0.0204
EpiControl
AF:
0.0207

ClinVar

Significance: Conflicting classifications of pathogenicity; association
Submissions summary: Pathogenic:3Uncertain:3Benign:6Other:3
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Pathogenic:1Benign:3
Pathogenic, criteria provided, single submitterclinical testingAiLife Diagnostics, AiLife DiagnosticsMar 31, 2022- -
Likely benign, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesOct 26, 2023- -
Likely benign, no assertion criteria providedclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center-- -
Likely benign, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, University Medical Center Utrecht-- -
Inflammatory bowel disease 1 Pathogenic:1Other:1
risk factor, no assertion criteria providedliterature onlyOMIMJan 31, 2017- -
Likely risk allele, no assertion criteria providedclinical testingLaboratory of Medical Genetics, National & Kapodistrian University of AthensAug 22, 2022- -
Blau syndrome Uncertain:1Benign:1
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJun 14, 2016- -
Uncertain significance, criteria provided, single submitterclinical testingMendelicsMay 28, 2019- -
Crohn’s Disease Pathogenic:1
Established risk allele, no assertion criteria providedresearchDepartment of Pathology and Laboratory Medicine, Sinai Health System-The NOD2 c.3019dupC (p.Leu1007fs) variant was identified in population-based control studies and family studies, showing an elevated risk of Crohn’s Disease compared to the general population (PMID: 21548950, 15024686, 18489434, 11425413, 11385576, 11385577, 11910337, 12019468, 15190267, 15571588) (ClinVar entry by Invitae, Accession: SCV000636103.6). A large meta-analysis of 75 case-control studies suggests the odds ratio for Crohn’s disease to be 3.8 for carriers of the variant (95% CI 3.4-4.3) (ID: 19713276) (ClinVar entry by Invitae, Accession: SCV000636103.6). Schnitzler et al. characterized the NOD2 genotype of 1066 patients with Crohn’s Disease, identifying 54 individuals homozygous for the p.Leu1007fs variant, 153 heterozygotes, and 25 compound heterozygotes (freq: 13.4%). The variant was present at a significantly higher frequency in individuals with aggressive disease (15.6%) compared to those with mild disease (8.2%) (p = 2.6 x 10-5). Of the 54 individuals homozygous for the variant, 100% had ileal disease, compared to 82% of NOD2 wild-type carriers (p<0.0001). In combination with active smoking, homozygosity for this variant is associated with 100% risk for developing ileal stenosis requiring Crohn’s Disease-related surgical intervention (Schnitzler_2020_PMID: 32716958). The variant was also identified in dbSNP (ID: rs2066847) and ClinVar (classified as uncertain and likely benign in association with Yao Syndrome by Mendelics and Illumina, respectively, classified as likely benign and an increased risk allele in association with Crohn Disease by Illumina and Invitae, respectively, classified as likely benign in association with Inflammatory Bowel Disease 1; Blau Syndrome by ARUP Laboratories, and benign by University Medical Center Groningen) databases. The variant was identified in control databases in 4,298 of 282,762 chromosomes (115 homozygous) at a frequency of 1.52%, and was observed at the highest frequency in the Ashkenazi Jewish population in 355 of 10,364 chromosomes (freq: 3.43%) (Genome Aggregation Database March 6, 2019, v2.1.1). Functional studies have shown the variant causes reduced cytokine production upon exposure to bacteria, but is capable of inducing T-cell polarization (ID: 18240302), reduced NFkB activity, reduced response to lipopolysaccharide and peptidoglycan (PMID: 12512038, 15198989), and impaired membrane association and signaling response upon stimulation of synthetic immunoreactive peptides (PMID: 26500656, 22684479, 21335489) (ClinVar entry by Invitae, Accession: SCV000636103.6). The c.3019dupC variant occurs within 50 base pairs of the penultimate exon-exon junction. Variants in this region may escape non-sense mediated RNA decay, therefore the clinical significance of this variant cannot be determined with certainty at this time. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. However, this variant may act as a risk factor for Crohn’s Disease. -
Autoinflammatory syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGenome Diagnostics Laboratory, The Hospital for Sick ChildrenMar 14, 2022- -
Yao syndrome;C5201146:Blau syndrome;CN260071:Inflammatory bowel disease 1 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingCenter for Genomics, Ann and Robert H. Lurie Children's Hospital of ChicagoOct 18, 2022This variant has been reported in the literature as a risk allele and identified as heterozygous and homozygous in several individuals with Crohn's disease as well as control individuals(Hampe 2001 PMID:11425413, Ogura 2001 PMID:11385577, Bonen 2003 PMID:12512038, Girardelli 2018 PMID:29248579). This variant is present in 2.3% (3012/129102) of European alleles, including 92 homozygotes in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/16-50763778-G-GC). This variant is present in ClinVar, with at least 1 entry classfying this variant as a risk allele (Variation ID:4691). Evolutionary conservation and computational predictive tools for this variant are unclear. Functional studies suggest a deleterious effect of this variant, reducing levels of NF-kB in response to bacterial lipopolysaccharide and peptidoglycan (Bonen 2003 PMID:12512038). However, further studies are needed to understand its impact. This variant is a duplication of 1 nucleotide and creates a premature stop codon 2 amino acids downstream from this location which results in an absent or abnormal protein. Of note, this variant occurs within the last two exons of this gene; due to its position, it is possible that this protein may escape nonsense mediated decay. Further studies are needed to understand its impact. In summary, data on this variant support that this variant does not act as a true mendelian disorder variant, but may increase risk for Crohn's disease. Therefore, the clinical significance of this variant is classified as a risk allele. -
not specified Benign:1
Benign, no assertion criteria providedclinical testingDiagnostic Laboratory, Department of Genetics, University Medical Center Groningen-- -
Crohn disease Benign:1
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJun 14, 2016- -
Yao syndrome Other:1
risk factor, no assertion criteria providedliterature onlyOMIMJan 31, 2017- -
Regional enteritis;C5201146:Blau syndrome Other:1
association, criteria provided, single submitterclinical testingInvitaeJan 31, 2024This sequence change creates a premature translational stop signal (p.Leu1007Profs*2) in the NOD2 gene. It is expected to result in an absent or disrupted protein product. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 34 amino acid(s) of the NOD2 protein. This variant is present in population databases (rs2066847, gnomAD 3%), including at least one homozygous and/or hemizygous individual. Population-based case-control studies and family studies have shown that this variant confers an elevated risk of Crohn's disease (PMID: 21548950, 15024686, 18489434, 11425413, 11385576, 11385577, 11910337, 12019468, 15190267, 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 = 3.8, 95% CI 3.4-4.3). 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 known as c.3020insC in the literature. ClinVar contains an entry for this variant (Variation ID: 4691). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this truncating variant conveys reduced production of cytokines upon bacterial exposure but is capable of inducing T-cell polarization (PMID: 18240302). This variant also demonstrated decreased NFkB activity and decreased response to lipopolysaccharide and peptidoglycan compared to wildtype protein (PMID: 12512038, 15198989), and impaired membrane association and signaling responses upon stimulation of synthetic immunoreactive peptides (PMID: 26500656, 22684479, 21335489). In summary, this is a frequently observed variant that is associated with approximately a 3.8-fold increased risk of Crohn's disease in population studies. Therefore, it has been classified as an Increased Risk Allele. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.050
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: rs2066847; hg19: chr16-50763778; API