chr16-50711203-C-T

Position:

chr16-50711203-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001370466.1(NOD2):c.1211C>T(p.Ser404Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00136 in 1,614,046 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00098 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0014 ( 9 hom. )

Consequence

NOD2
NM_001370466.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:5O:1

Conservation

PhyloP100: 2.53

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:

NOD2 (HGNC:):

NOD2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.049495965).

BP6

Variant 16-50711203-C-T is Benign according to our data. Variant chr16-50711203-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 97826.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=1, not_provided=1, Benign=1}. Variant chr16-50711203-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000978 (149/152346) while in subpopulation NFE AF= 0.00187 (127/68036). AF 95% confidence interval is 0.0016. There are 0 homozygotes in gnomad4. There are 61 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 9 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NOD2	NM_001370466.1 linkuse as main transcript	c.1211C>T	p.Ser404Leu	missense_variant	4/12	ENST00000647318.2	NP_001357395.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
NOD2	ENST00000647318.2 linkuse as main transcript	c.1211C>T	p.Ser404Leu	missense_variant	4/12		NM_001370466.1	ENSP00000495993.1	Q9HC29-2
NOD2	ENST00000300589.6 linkuse as main transcript	c.1292C>T	p.Ser431Leu	missense_variant	4/12	1		ENSP00000300589.2	Q9HC29-1
NOD2	ENST00000641284.2 linkuse as main transcript	n.1211C>T		non_coding_transcript_exon_variant	4/6			ENSP00000493088.1	A0A286YF65
NOD2	ENST00000646677.2 linkuse as main transcript	n.1211C>T		non_coding_transcript_exon_variant	4/13			ENSP00000496533.1	A0A286YF65

Frequencies

GnomAD3 genomes

AF:

0.000979

AC:

149

AN:

152228

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000410

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

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:

0.00187

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000965

AC:

242

AN:

250764

Hom.:

AF XY:

0.000943

AC XY:

128

AN XY:

135668

show subpopulations

Gnomad AFR exome

AF:

0.000371

Gnomad AMR exome

AF:

0.000752

Gnomad ASJ exome

AF:

0.0000994

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000392

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00167

Gnomad OTH exome

AF:

0.00131

GnomAD4 exome

AF:

0.00140

AC:

2047

AN:

1461700

Hom.:

Cov.:

AF XY:

0.00139

AC XY:

1013

AN XY:

727172

show subpopulations

Gnomad4 AFR exome

AF:

0.000358

Gnomad4 AMR exome

AF:

0.000671

Gnomad4 ASJ exome

AF:

0.0000765

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000383

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00171

Gnomad4 OTH exome

AF:

0.00103

GnomAD4 genome

AF:

0.000978

AC:

149

AN:

152346

Hom.:

Cov.:

AF XY:

0.000819

AC XY:

AN XY:

74492

show subpopulations

Gnomad4 AFR

AF:

0.000409

Gnomad4 AMR

AF:

0.000327

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00187

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00135

Hom.:

Bravo

AF:

0.00102

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.000455

AC:

ESP6500EA

AF:

0.00140

AC:

ExAC

AF:

0.000824

AC:

100

EpiCase

AF:

0.00164

EpiControl

AF:

0.00178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:5Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 01, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	NOD2: BP4, BS1 -

Blau syndrome

Benign:1Other:1

not provided, no classification provided	literature only	Unité médicale des maladies autoinflammatoires, CHRU Montpellier	-	- -
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. -

Inflammatory bowel disease 1

Uncertain:1

Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

NOD2-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 22, 2023

The NOD2 c.1292C>T variant is predicted to result in the amino acid substitution p.Ser431Leu. This variant has been reported in individuals with inflammatory bowel disease or Crohn’s disease (Lesage et al. 2002. PubMed ID: 11875755; Rivas et al. 2011. PubMed ID: 21983784). Of note, this variant was also reported in patients with childhood onset inflammatory bowel disease (pIBD) (Andreoletti et al. 2017. PubMed ID: 28422189; Chen et al. 2018. PubMed ID: 30166421). This variant was also reported in the presence of additional NOD2 variants [c.2377G>A (p.Val793Met) and c.2798+158C>T] in at least two patients with NOD2-associated autoinflammatory disease (Yao et al. 2015. PubMed ID: 26070941). This variant was also reported in one individual in a study of patients with inherited retinal and optical nerve disorders (Table S12, Diñeiro et al. 2020. PubMed ID: 32483926) and was identified in an individual with orofacial granulomatosis (Mentzer et al. 2016. PubMed ID: 27306066). Functional studies showed that this variant altered NOD2 protein localization and function (Rivas et al. 2011. PubMed ID: 21983784). This variant is reported in 0.16% of alleles in individuals of European (Non-Finnish) descent in gnomAD, including two homozygous individuals and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from uncertain significance to likely benign to benign (https://www.ncbi.nlm.nih.gov/clinvar/variation/97826/). However, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Regional enteritis;C5201146:Blau syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 27, 2024

- -

Autoinflammatory syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jun 01, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.29

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.26

.;T

Eigen

Benign

0.17

Eigen_PC

Benign

0.16

FATHMM_MKL

Uncertain

0.78

LIST_S2

Uncertain

0.92

D;D

M_CAP

Pathogenic

0.30

MetaRNN

Benign

0.049

T;T

MetaSVM

Benign

-0.46

MutationAssessor

Uncertain

2.2

.;M

PrimateAI

Benign

0.38

PROVEAN

Benign

-2.0

.;N

REVEL

Uncertain

0.36

Sift

Benign

0.046

.;D

Sift4G

Uncertain

0.040

.;D

Polyphen

0.81

P;P

Vest4

0.30

MVP

0.94

MPC

0.13

ClinPred

0.015

GERP RS

4.3

Varity_R

0.095

gMVP

0.39

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