rs104895456

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_ModerateBP6

The NM_001370466.1(NOD2):​c.332G>A​(p.Arg111Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00014 in 1,613,572 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R111W) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000092 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00015 ( 0 hom. )

Consequence

NOD2
NM_001370466.1 missense

Scores

2
8
9

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2O:1

Conservation

PhyloP100: 5.54
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.16849265).
BP6
Variant 16-50699827-G-A is Benign according to our data. Variant chr16-50699827-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 97877.We mark this variant Likely_benign, oryginal submissions are: {not_provided=1, Likely_benign=2, Uncertain_significance=1}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
NOD2NM_001370466.1 linkuse as main transcriptc.332G>A p.Arg111Gln missense_variant 2/12 ENST00000647318.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
NOD2ENST00000647318.2 linkuse as main transcriptc.332G>A p.Arg111Gln missense_variant 2/12 NM_001370466.1 P1Q9HC29-2

Frequencies

GnomAD3 genomes
AF:
0.0000920
AC:
14
AN:
152190
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000121
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000118
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.0000758
AC:
19
AN:
250786
Hom.:
0
AF XY:
0.0000885
AC XY:
12
AN XY:
135616
show subpopulations
Gnomad AFR exome
AF:
0.000123
Gnomad AMR exome
AF:
0.0000868
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000123
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000145
AC:
212
AN:
1461264
Hom.:
0
Cov.:
33
AF XY:
0.000135
AC XY:
98
AN XY:
726928
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.000112
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000171
Gnomad4 OTH exome
AF:
0.000265
GnomAD4 genome
AF:
0.0000919
AC:
14
AN:
152308
Hom.:
0
Cov.:
32
AF XY:
0.0000940
AC XY:
7
AN XY:
74470
show subpopulations
Gnomad4 AFR
AF:
0.000120
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000118
Gnomad4 OTH
AF:
0.000473
Alfa
AF:
0.000126
Hom.:
0
Bravo
AF:
0.0000907
ESP6500AA
AF:
0.000227
AC:
1
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.0000824
AC:
10
EpiCase
AF:
0.000273
EpiControl
AF:
0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:2Other:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Blau syndrome Benign:1Other:1
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 provided, no classification providedliterature onlyUnité médicale des maladies autoinflammatoires, CHRU Montpellier-- -
Regional enteritis;C5201146:Blau syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpOct 14, 2023This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 138 of the NOD2 protein (p.Arg138Gln). This variant is present in population databases (rs104895456, gnomAD 0.02%). This missense change has been observed in individual(s) with Crohn's disease (PMID: 11875755). ClinVar contains an entry for this variant (Variation ID: 97877). 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 affects NOD2 function (PMID: 12626759, 26500656). 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. -
Inflammatory bowel disease 1 Benign:1
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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.42
BayesDel_addAF
Benign
-0.24
T
BayesDel_noAF
Benign
-0.27
CADD
Pathogenic
27
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.49
.;.;T
Eigen
Uncertain
0.38
Eigen_PC
Uncertain
0.46
FATHMM_MKL
Uncertain
0.93
D
LIST_S2
Benign
0.85
T;T;T
M_CAP
Benign
0.029
D
MetaRNN
Benign
0.17
T;T;T
MetaSVM
Benign
-0.96
T
MutationAssessor
Uncertain
2.6
.;.;M
MutationTaster
Benign
1.0
D
PrimateAI
Benign
0.41
T
PROVEAN
Uncertain
-3.7
.;D;N
REVEL
Benign
0.17
Sift
Uncertain
0.017
.;D;D
Sift4G
Pathogenic
0.0
.;D;D
Polyphen
0.73
.;.;P
Vest4
0.52
MVP
0.79
MPC
0.36
ClinPred
0.37
T
GERP RS
5.3
Varity_R
0.22
gMVP
0.74

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: rs104895456; hg19: chr16-50733738; API