chr16-50711203-C-T

Variant names:

• chr16-50711203-C-T
• rs104895431
• NM_001370466.1:c.1211C>T

Variant summary

Our verdict is Benign. The variant received -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. 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
• Publications: 35 publications found

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 Gene-Disease associations (from GenCC):

• Blau syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet, Genomics England PanelApp, G2P, Illumina, Labcorp Genetics (formerly Invitae)
• inflammatory bowel disease 1

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -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 Benign, oryginal submissions are: {Uncertain_significance=1, Benign=1, other=1, Likely_benign=4}.
• 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 149 AD,Unknown gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOD2	NM_001370466.1	c.1211C>T	p.Ser404Leu	missense_variant	Exon 4 of 12	ENST00000647318.2	NP_001357395.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOD2	ENST00000647318.2	c.1211C>T	p.Ser404Leu	missense_variant	Exon 4 of 12		NM_001370466.1	ENSP00000495993.1
NOD2	ENST00000300589.6	c.1292C>T	p.Ser431Leu	missense_variant	Exon 4 of 12	1		ENSP00000300589.2
NOD2	ENST00000641284.2	n.1211C>T		non_coding_transcript_exon_variant	Exon 4 of 6			ENSP00000493088.1
NOD2	ENST00000646677.2	n.1211C>T		non_coding_transcript_exon_variant	Exon 4 of 13			ENSP00000496533.1

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

GnomAD2 exomes AF: 0.000965 AC: 242 AN: 250764 AF XY: 0.000943

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 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

African (AFR) AF: 0.000358 AC: 12 AN: 33480

American (AMR) AF: 0.000671 AC: 30 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000765 AC: 2 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.000383 AC: 33 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53240

Middle Eastern (MID) AF: 0.000693 AC: 4 AN: 5768

European-Non Finnish (NFE) AF: 0.00171 AC: 1903 AN: 1112010

Other (OTH) AF: 0.00103 AC: 62 AN: 60394

GnomAD4 genome AF: 0.000978 AC: 149 AN: 152346 Hom.: 0 Cov.: 33 AF XY: 0.000819 AC XY: 61 AN XY: 74492

African (AFR) AF: 0.000409 AC: 17 AN: 41584

American (AMR) AF: 0.000327 AC: 5 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00187 AC: 127 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.00139 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

Nov 01, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NOD2: BP4, BS1 -

Blau syndrome Benign:1 Other:1

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

-

Unité médicale des maladies autoinflammatoires, CHRU Montpellier

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Inflammatory bowel disease 1 Uncertain:1

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Dec 22, 2023

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autoinflammatory syndrome Benign:1

Jun 01, 2020

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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
DEOGEN2	Benign	0.26	.;T
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
MutationAssessor	Uncertain	2.2	.;M
PhyloP100		2.5
PrimateAI	Benign	0.38	T
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	T
GERP RS		4.3
Varity_R		0.095
gMVP		0.39
Mutation Taster		=87/13	polymorphism

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

Other links and lift over

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