rs104895423

Positions:

chr16-50710654-T-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 1P and 10B. PP3BP4_ModerateBS1BS2

The NM_001370466.1(NOD2):c.662T>G(p.Leu221Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000381 in 1,614,204 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00028 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00039 ( 6 hom. )

Consequence

NOD2
NM_001370466.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:2O:1

Conservation

PhyloP100: 7.36

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]

NOD2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

PP3

Multiple lines of computational evidence support a deleterious effect 8: AlphaMissense, BayesDel_addAF, BayesDel_noAF, Cadd, Eigen, M_CAP, MutationAssessor, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.10175744).

BS1

Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000391 (572/1461880) while in subpopulation MID AF= 0.00277 (16/5768). AF 95% confidence interval is 0.00174. There are 6 homozygotes in gnomad4_exome. There are 291 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 6 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NOD2	NM_001370466.1 linkuse as main transcript	c.662T>G	p.Leu221Arg	missense_variant	4/12	ENST00000647318.2	NP_001357395.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NOD2	ENST00000647318.2 linkuse as main transcript	c.662T>G	p.Leu221Arg	missense_variant	4/12		NM_001370466.1	ENSP00000495993	P1	Q9HC29-2

Frequencies

GnomAD3 genomes

AF:

0.000283

AC:

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00317

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000353

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.000561

AC:

141

AN:

251368

Hom.:

AF XY:

0.000537

AC XY:

AN XY:

135864

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.000231

Gnomad ASJ exome

AF:

0.00546

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000545

Gnomad OTH exome

AF:

0.00163

GnomAD4 exome

AF:

0.000391

AC:

572

AN:

1461880

Hom.:

Cov.:

AF XY:

0.000400

AC XY:

291

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.000201

Gnomad4 ASJ exome

AF:

0.00524

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000927

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000315

Gnomad4 OTH exome

AF:

0.000811

GnomAD4 genome

AF:

0.000282

AC:

AN:

152324

Hom.:

Cov.:

AF XY:

0.000228

AC XY:

AN XY:

74484

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000261

Gnomad4 ASJ

AF:

0.00317

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000353

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.000778

Hom.:

Bravo

AF:

0.000351

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000581

AC:

ExAC

AF:

0.000560

AC:

EpiCase

AF:

0.000654

EpiControl

AF:

0.000830

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:2Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 06, 2020	The NOD2 c.743T>G; p.Leu248Arg variant (rs104895423) is reported in one individual with diagnoses of Behcet and Crohn's disease (Burillo-Sanz 2017) and in several individuals with Crohn's disease or inflammatory bowel disease (Girardelli 2018, Lesage 2002, Rivas 2018, Schiff 2018). The variant is reported in the general population with an overall allele frequency of 0.05% (147/282,764 alleles including 2 homozygotes) in the Genome Aggregation Database and is listed in the ClinVar database (Variation ID: 97881). The leucine at codon 248 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Additionally, functional studies show this variant protein does not associate with the membrane or respond to signals as the wild type protein (Parkhouse and Monie 2015). This variant may be a risk factor for Crohn's disease, possibly contributing together with other genetic and/or environmental factors. However, the significance of this variant specifically associated with a periodic fever disease such as Blau syndrome remains uncertain. References: Burillo-Sanz S et al. Mutational profile of rare variants in inflammasome-related genes in Behcet disease: A Next Generation Sequencing approach. Sci Rep. 2017 Aug 16;7(1):8453. Girardelli M et al. Genetic profile of patients with early onset inflammatory bowel disease. Gene. 2018 Mar 1;645:18-29. Lesage S et al. CARD15/NOD2 mutational analysis and genotype-phenotype correlation in 612 patients with inflammatory bowel disease. Am J Hum Genet. 2002 Apr;70(4):845-57. Parkhouse R and Monie TP. Dysfunctional Crohn's Disease-Associated NOD2 Polymorphisms Cannot be Reliably Predicted on the Basis of RIPK2 Binding or Membrane Association. Front Immunol. 2015 Oct 8;6:521. Rivas MA et al. Insights into the genetic epidemiology of Crohn's and rare diseases in the Ashkenazi Jewish population. PLoS Genet. 2018 May 24;14(5):e1007329. Schiff ER et al. Rare coding variant analysis in a large cohort of Ashkenazi Jewish families with inflammatory bowel disease. Hum Genet. 2018 Sep;137(9):723-734. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 23, 2024	Identified in association with inflammatory bowel disease and Crohn's disease, however, detailed clinical information and segregation information were not always provided (PMID: 11875755, 29248579, 29795570, 33692434); Also identified in association with the following disorders: Behcet disease, inherited retinal and optical nerve disorder, and pediatric encephalitis, however, clinical and segregation information were not provided, and additional variants were identified in other genes in some of these individuals (PMID: 28814775, 32483926, 36198812); Functional studies performed on this variant have produced inconclusive results (PMID: 26500656, 38187608); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 11875755, 30167848, 28814775, 29248579, 32222431, 32483926, 29795570, 33692434, 38187608, 36006803, 37080976, 36198812, 36049483, 34347074, 26500656) -

Blau syndrome

Uncertain:1Other:1

not provided, no classification provided	literature only	Unité médicale des maladies autoinflammatoires, CHRU Montpellier	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	May 30, 2018	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Regional enteritis;C5201146:Blau syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 04, 2024

- -

Autoinflammatory syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Dec 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.63

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Pathogenic

0.36

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.66

.;D

Eigen

Pathogenic

0.69

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.86

D;D

M_CAP

Pathogenic

0.58

MetaRNN

Benign

0.10

T;T

MetaSVM

Uncertain

0.37

MutationAssessor

Pathogenic

3.2

.;M

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.57

PROVEAN

Uncertain

-4.3

.;D

REVEL

Pathogenic

0.85

Sift

Pathogenic

0.0

.;D

Sift4G

Pathogenic

0.0

.;D

Polyphen

1.0

D;D

Vest4

0.77

MVP

0.93

MPC

0.60

ClinPred

0.15

GERP RS

5.3

Varity_R

0.79

gMVP

0.94

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over