rs104895431

chr16-50711203-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

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). Synonymous variant affecting the same amino acid position (i.e. S404S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00098 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0014 (9 hom.)
• Consequence: NOD2 NM_001370466.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:5 O:1
• Conservation: PhyloP100: 2.53

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]

ACMG classification

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=3, Uncertain_significance=2, Benign=2, not_provided=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. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 2 AD,AR gene

Transcripts

RefSeq

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

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NOD2	ENST00000647318.2	c.1211C>T	p.Ser404Leu	missense_variant	4/12		NM_001370466.1	P1
NOD2	ENST00000300589.6	c.1292C>T	p.Ser431Leu	missense_variant	4/12	1
NOD2	ENST00000641284.2	c.1211C>T	p.Ser404Leu	missense_variant, NMD_transcript_variant	4/6
NOD2	ENST00000646677.2	c.1211C>T	p.Ser404Leu	missense_variant, NMD_transcript_variant	4/13

Frequencies

GnomAD3 genomes AF: 0.000979 AC: 149 AN: 152228 Hom.: 0 Cov.: 33

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.: 2 AF XY: 0.000943 AC XY: 128 AN XY: 135668

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.: 9 Cov.: 40 AF XY: 0.00139 AC XY: 1013 AN XY: 727172

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.: 0 Cov.: 33 AF XY: 0.000819 AC XY: 61 AN XY: 74492

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.: 0

Bravo AF: 0.00102

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000455 AC: 2

ESP6500EA AF: 0.00140 AC: 12

ExAC AF: 0.000824 AC: 100

EpiCase AF: 0.00164

EpiControl AF: 0.00178

ClinVar

Significance: Conflicting classifications of pathogenicity

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

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2022	NOD2: BS1, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 01, 2023	- -

Blau syndrome Benign:1 Other: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	-	- -

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, criteria provided, single submitter

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

Invitae

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	T
BayesDel_noAF	Benign	-0.29
Cadd	Benign	19
Dann	Uncertain	1.0
Eigen	Benign	0.17
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Uncertain	0.92	D;D
M_CAP	Pathogenic	0.30	D
MetaRNN	Benign	0.049	T;T
MetaSVM	Benign	-0.46	T
MutationTaster	Benign	0.99	N
PrimateAI	Benign	0.38	T
Polyphen		0.81	P;P
Vest4		0.30
MVP		0.94
MPC		0.13
ClinPred		0.015	T
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

Other links and lift over

dbSNP: rs104895431; hg19: chr16-50745114; COSMIC: COSV100319010; COSMIC: COSV100319010;