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rs2066845

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_001370466.1(NOD2):c.2641G>C(p.Gly881Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0103 in 152170 control chromosomes in the gnomAD Genomes database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting interpretations of pathogenicity,association (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G881C) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.010 ( 9 hom., cov: 32)
Exomes 𝑓: 0.011 ( 43 hom. )

Consequence

NOD2
NM_001370466.1 missense

Scores

5
2
5

Clinical Significance

Conflicting classifications of pathogenicity; association criteria provided, conflicting classifications U:5B:4O:3

Conservation

PhyloP100: 4.50

Links

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4
?
Computational evidence support a benign effect (MetaRNN=0.010364234).
BS1
?
Variant frequency is greater than expected. gnomad allele frequency = 0.0103 (1571/152170) while in subpopulation NFE AF= 0.0147 (997/68018). AF 95% confidence interval is 0.0139. There are 9 homozygotes in gnomad. There are 742 alleles in male gnomad subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
?
High Homozygotes in GnomAd at 9 AD,AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
NOD2NM_001370466.1 linkuse as main transcriptc.2641G>C p.Gly881Arg missense_variant 8/12 ENST00000647318.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
NOD2ENST00000647318.2 linkuse as main transcriptc.2641G>C p.Gly881Arg missense_variant 8/12 NM_001370466.1 P1Q9HC29-2

Frequencies

GnomAD3 genomes
AF:
0.0103
AC:
1571
AN:
152170
Hom.:
9
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00275
Gnomad AMI
AF:
0.00219
Gnomad AMR
AF:
0.0139
Gnomad ASJ
AF:
0.0432
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00579
Gnomad FIN
AF:
0.00254
Gnomad MID
AF:
0.0222
Gnomad NFE
AF:
0.0147
Gnomad OTH
AF:
0.0163
GnomAD3 exomes
AF:
0.0113
AC:
2837
AN:
251458
Hom.:
43
AF XY:
0.0118
AC XY:
1606
AN XY:
135898
show subpopulations
Gnomad AFR exome
AF:
0.00160
Gnomad AMR exome
AF:
0.00890
Gnomad ASJ exome
AF:
0.0463
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00800
Gnomad FIN exome
AF:
0.00309
Gnomad NFE exome
AF:
0.0143
Gnomad OTH exome
AF:
0.0165
GnomAD4 exome
AF:
0.0131
AC:
19221
AN:
1461816
Hom.:
236
AF XY:
0.0133
AC XY:
9644
AN XY:
727210
show subpopulations
Gnomad4 AFR exome
AF:
0.00227
Gnomad4 AMR exome
AF:
0.00854
Gnomad4 ASJ exome
AF:
0.0423
Gnomad4 EAS exome
AF:
0.0000504
Gnomad4 SAS exome
AF:
0.00907
Gnomad4 FIN exome
AF:
0.00292
Gnomad4 NFE exome
AF:
0.0141
Gnomad4 OTH exome
AF:
0.0135
Alfa
AF:
0.0142
Hom.:
24
Bravo
AF:
0.0101
TwinsUK
AF:
0.0148
AC:
55
ALSPAC
AF:
0.0117
AC:
45
ESP6500AA
AF:
0.00159
AC:
7
ESP6500EA
AF:
0.0145
AC:
125
ExAC
AF:
0.00992
AC:
1204
Asia WGS
AF:
0.00433
AC:
15
AN:
3478
EpiCase
AF:
0.0164
EpiControl
AF:
0.0151

ClinVar

Significance: Conflicting classifications of pathogenicity; association
Submissions summary: Uncertain:5Benign:4Other:3
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Inflammatory bowel disease 1 Uncertain:1Benign:1Other:1
risk factor, no assertion criteria providedliterature onlyOMIMJul 01, 2002- -
Uncertain significance, criteria provided, single submitterclinical testingAl Jalila Children's Genomics Center, Al Jalila Childrens Speciality HospitalDec 10, 2020- -
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaApr 27, 2017This 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. -
not provided Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenMar 01, 2017- -
Likely benign, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesJun 22, 2022- -
Blau syndrome Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitterclinical testingMendelicsMay 28, 2019- -
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaApr 27, 2017This 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. -
not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGenomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of PhiladelphiaNov 11, 2015- -
Psoriatic arthritis, susceptibility to;C4310620: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 ChicagoApr 15, 2021NOD2 NM_022162.2 exon 8 p.Gly908Arg (c.2722G>C):This variant has been reported in the literature in numerous individuals with a variety of phenotypes, most often in the context of immunological related presentations such as Crohn's disease or Irritable Bowel Disease (IBD) (Hugot 2001 PMID:11385576, Cuthbert 2002 PMID:11910337, Bonen 2003 PMID:12512038, Kabesch 2003 PMID:12704363, Girardelli 2018 PMID:29248579, Hui 2018 PMID:29321258, Gonzalez-Mancera 2020 PMID:32654169). In a large meta analysis study (PMID: 19713276), Individuals carrying this variant had an increased overall risk of Crohn's disease (OR = 2.6, 95% CI 2.2-2.9). However, this variant is present in several control individuals in the literature and is present in 1.4% (997/68018) of European alleles, including 5 homozygotes in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/16-50722629-G-C?dataset=gnomad_r3). This variant is present in ClinVar (Variation ID:4692) with classifications ranging from Variant of Uncertain Significance to Likely Benign as well as at least 1 entry as a Risk Allele. Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In vitro functional studies predict that this variant will impact the protein (Bonen 2003 PMID:12512038). However, these studies may not accurately represent in vivo biological function. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain but given the available data, the classification of this variant is likely most appropriate as a risk allele. -
Autoinflammatory syndrome Benign:1
Benign, criteria provided, single submitterclinical testingGenome Diagnostics Laboratory, The Hospital for Sick ChildrenFeb 05, 2022- -
Yao syndrome Other:1
risk factor, no assertion criteria providedliterature onlyOMIMJul 01, 2002- -
Regional enteritis;C5201146:Blau syndrome Other:1
association, criteria provided, single submitterclinical testingInvitaeNov 03, 2022This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 908 of the NOD2 protein (p.Gly908Arg). This variant is present in population databases (rs2066845, gnomAD 5%), 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: 21548950, 15024686, 18489434, 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 = 2.6, 95% CI 2.2-2.9). 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 G881R in the literature. ClinVar contains an entry for this variant (Variation ID: 4692). 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. Experimental studies have shown that this missense change results in decreased NFkB activity and decreased response to lipopolysaccharide and peptidoglycan compared to wildtype protein (PMID: 12512038, 15198989). In summary, this is a frequently observed variant that is associated with approximately a 2.6-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
AlphaMissense
Pathogenic
0.85
BayesDel_addAF
Benign
-0.076
T
BayesDel_noAF
Pathogenic
0.14
Cadd
Pathogenic
27
Dann
Pathogenic
1.0
Eigen
Pathogenic
0.77
Eigen_PC
Pathogenic
0.78
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Benign
0.77
T;T
MetaRNN
Benign
0.010
T;T
MetaSVM
Benign
-0.70
T
MutationTaster
Benign
1.0
D
PrimateAI
Uncertain
0.64
T
Polyphen
1.0
D;D
Vest4
0.75
MPC
0.54
ClinPred
0.029
T
GERP RS
5.9
Varity_R
0.83
gMVP
0.56

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
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: rs2066845; hg19: chr16-50756540; COSMIC: COSV56054563; COSMIC: COSV56054563; API