rs5743291

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001370466.1(NOD2):c.2782G>A(p.Val928Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0772 in 1,613,456 control chromosomes in the GnomAD database, including 5,597 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.060 ( 390 hom., cov: 32)

Exomes 𝑓: 0.079 ( 5207 hom. )

Consequence

NOD2
NM_001370466.1 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10O:1

Conservation

PhyloP100: -1.22

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0018509626).

BP6

Variant 16-50723365-G-A is Benign according to our data. Variant chr16-50723365-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 97869.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-50723365-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0873 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NOD2	NM_001370466.1 linkuse as main transcript	c.2782G>A	p.Val928Ile	missense_variant	9/12	ENST00000647318.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NOD2	ENST00000647318.2 linkuse as main transcript	c.2782G>A	p.Val928Ile	missense_variant	9/12		NM_001370466.1	P1	Q9HC29-2

Frequencies

GnomAD3 genomes

AF:

0.0602

AC:

9154

AN:

152104

Hom.:

390

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0165

Gnomad AMI

AF:

0.120

Gnomad AMR

AF:

0.0658

Gnomad ASJ

AF:

0.178

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.0182

Gnomad FIN

AF:

0.0364

Gnomad MID

AF:

0.0737

Gnomad NFE

AF:

0.0892

Gnomad OTH

AF:

0.0820

GnomAD3 exomes

AF:

0.0627

AC:

15757

AN:

251364

Hom.:

723

AF XY:

0.0636

AC XY:

8643

AN XY:

135840

show subpopulations

Gnomad AFR exome

AF:

0.0141

Gnomad AMR exome

AF:

0.0510

Gnomad ASJ exome

AF:

0.171

Gnomad EAS exome

AF:

0.000652

Gnomad SAS exome

AF:

0.0206

Gnomad FIN exome

AF:

0.0393

Gnomad NFE exome

AF:

0.0885

Gnomad OTH exome

AF:

0.0792

GnomAD4 exome

AF:

0.0789

AC:

115358

AN:

1461234

Hom.:

5207

Cov.:

AF XY:

0.0776

AC XY:

56440

AN XY:

726936

show subpopulations

Gnomad4 AFR exome

AF:

0.0131

Gnomad4 AMR exome

AF:

0.0524

Gnomad4 ASJ exome

AF:

0.175

Gnomad4 EAS exome

AF:

0.000479

Gnomad4 SAS exome

AF:

0.0214

Gnomad4 FIN exome

AF:

0.0399

Gnomad4 NFE exome

AF:

0.0886

Gnomad4 OTH exome

AF:

0.0818

GnomAD4 genome

AF:

0.0601

AC:

9149

AN:

152222

Hom.:

390

Cov.:

AF XY:

0.0562

AC XY:

4180

AN XY:

74428

show subpopulations

Gnomad4 AFR

AF:

0.0165

Gnomad4 AMR

AF:

0.0657

Gnomad4 ASJ

AF:

0.178

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.0182

Gnomad4 FIN

AF:

0.0364

Gnomad4 NFE

AF:

0.0892

Gnomad4 OTH

AF:

0.0806

Alfa

AF:

0.0886

Hom.:

1720

Bravo

AF:

0.0614

TwinsUK

AF:

0.0947

AC:

351

ALSPAC

AF:

0.0859

AC:

331

ESP6500AA

AF:

0.0162

AC:

ESP6500EA

AF:

0.0960

AC:

826

ExAC

AF:

0.0608

AC:

7387

Asia WGS

AF:

0.0120

AC:

AN:

3478

EpiCase

AF:

0.0967

EpiControl

AF:

0.0987

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Inflammatory bowel disease 1

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Al Jalila Children's Genomics Center, Al Jalila Childrens Speciality Hospital	Jun 21, 2020	- -

Blau syndrome

Benign:1Other:1

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
not provided, no classification provided	literature only	Unité médicale des maladies autoinflammatoires, CHRU Montpellier	-	- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Nov 27, 2023

- -

Regional enteritis;C5201146:Blau syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Autoinflammatory syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jan 29, 2022

- -

Psoriatic arthritis, susceptibility to;C4310620:Yao syndrome;C5201146:Blau syndrome;CN260071:Inflammatory bowel disease 1

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.079

BayesDel_addAF

Benign

-0.64

BayesDel_noAF

Benign

-0.63

Cadd

Benign

0.63

Dann

Benign

0.85

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.0080

LIST_S2

Benign

0.64

T;T

MetaRNN

Benign

0.0019

T;T

MetaSVM

Benign

-1.1

MutationTaster

Benign

1.0

PrimateAI

Benign

0.26

Polyphen

0.51

P;P

Vest4

0.035

MPC

0.12

ClinPred

0.0034

GERP RS

-6.4

Varity_R

0.017

gMVP

0.080

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