16-50729867-GC-GCC

Variant names:

• chr16-50729867-G-GC
• rs2066847
• NM_001370466.1:c.2938dupC

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PVS1_Moderate BS1_Supporting BS2

The NM_001370466.1(NOD2):​c.2938dupC​(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: 𝑓 0.015 (30 hom., cov: 32)
  • Exomes 𝑓: 0.018 (577 hom.)
• Consequence: NOD2 NM_001370466.1 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity; association criteria provided, conflicting classifications P:3 U:5 B:6 O:4
• Conservation: PhyloP100: 1.98
• Publications: 375 publications found

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)

ACMG classification

Our verdict: Likely_benign. The variant received -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 0.0339 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 2274 AD,Unknown gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOD2	NM_001370466.1	c.2938dupC	p.Leu980ProfsTer2	frameshift_variant	Exon 11 of 12	ENST00000647318.2	NP_001357395.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOD2	ENST00000647318.2	c.2938dupC	p.Leu980ProfsTer2	frameshift_variant	Exon 11 of 12		NM_001370466.1	ENSP00000495993.1

Frequencies

GnomAD3 genomes AF: 0.0149 AC: 2274 AN: 152166 Hom.: 30 Cov.: 32

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

GnomAD2 exomes AF: 0.0150 AC: 3771 AN: 251370 AF XY: 0.0149

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 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

African (AFR) AF: 0.00236 AC: 79 AN: 33456

American (AMR) AF: 0.00803 AC: 359 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.0322 AC: 841 AN: 26098

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39674

South Asian (SAS) AF: 0.00160 AC: 138 AN: 86236

European-Finnish (FIN) AF: 0.0147 AC: 784 AN: 53372

Middle Eastern (MID) AF: 0.00261 AC: 15 AN: 5758

European-Non Finnish (NFE) AF: 0.0215 AC: 23942 AN: 1111282

Other (OTH) AF: 0.0136 AC: 823 AN: 60328

GnomAD4 genome AF: 0.0149 AC: 2274 AN: 152284 Hom.: 30 Cov.: 32 AF XY: 0.0145 AC XY: 1077 AN XY: 74460

African (AFR) AF: 0.00344 AC: 143 AN: 41564

American (AMR) AF: 0.0131 AC: 201 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0285 AC: 99 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.0182 AC: 193 AN: 10610

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0231 AC: 1570 AN: 68018

Other (OTH) AF: 0.0180 AC: 38 AN: 2110

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:3 Uncertain:5 Benign:6 Other:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Uncertain:1 Benign:3

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 31, 2022

AiLife Diagnostics, AiLife Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 19, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 22, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Frameshift variant predicted to result in abnormal protein length as the last 34 amino acids are replaced with 1 different amino acids in a gene for which loss-of-function is not known mechanism of disease; This variant is associated with the following publications: (PMID: 24586700, 34975878, 32716958, 22344438, 19103559, 19641059, 26167078, 21951874, 21745302, 19185283, 22543157, 24047397, 21565239, 23173613, 12704363, 19748964, 23633568, 20713205, 19184348, 19184350, 21548950, 18942754, 20332463, 26042516, 24597572, 21994160, 25365249, 20047977, 21460759, 19713276, 23615072, 22939045, 12512038, 29867916, 28750667, 29248579, 28658209, 29321258, 29178652, 28008999, 17301648, 16010583, 30166421, 11910337, 16669960, 27373512, 16416181, 29795570, 30167848, 30552907, 30553995, 28422189, 22440928, 22275320, 24345423, 23128233, 32597225, 27306066, 29446656, 12673278, 12650796, 17489054, 35743704, 31345219, 28819537, 34788239, 21983784, 11385577, 21335489, 19349988, 22684479, 19397946, 32463623, 33692434, 15002819, 23709157, 26070941, 11425413) -

Inflammatory bowel disease 1 Pathogenic:1 Uncertain:1 Other:1

Aug 22, 2022

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Significance: Likely risk allele

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 31, 2017

OMIM

Significance: risk factor

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Aug 22, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

- -

Blau syndrome Uncertain:1 Benign:1

May 28, 2019

Mendelics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Crohn’s Disease Pathogenic:1

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Established risk allele

Review Status: no assertion criteria provided

Collection Method: research

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

Mar 14, 2022

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Yao syndrome;C5201146:Blau syndrome;CN260071:Inflammatory bowel disease 1 Uncertain:1

-

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This 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

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Crohn disease Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Yao syndrome Other:1

Jan 31, 2017

OMIM

Significance: risk factor

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Regional enteritis;C5201146:Blau syndrome Other:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: association

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This 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 gene product 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. -

Crohn disease;C5201146:Blau syndrome Other:1

-

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant classified as Increased risk allele and reported on 12-23-2022 by Invitae. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.0
Mutation Taster		=146/54	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2066847; hg19: chr16-50763778; COSMIC: COSV56054506;