NM_001370466.1:c.2717+158C>T

Variant names:

• chr16-50722863-C-T
• rs5743289
• NM_001370466.1:c.2717+158C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_001370466.1(NOD2):​c.2717+158C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.109 in 152,166 control chromosomes in the GnomAD database, including 1,256 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 0.11 (1256 hom., cov: 32)
• Consequence: NOD2 NM_001370466.1 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:3 B:4 O:2
• Conservation: PhyloP100: -1.58
• Publications: 69 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 (BayesDel_noAF=-0.9).
• BP6: Variant 16-50722863-C-T is Benign according to our data. Variant chr16-50722863-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 4697.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.172 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001370466.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOD2	NM_001370466.1	MANE Select	c.2717+158C>T		intron	N/A	NP_001357395.1
	NOD2	NM_022162.3		c.2798+158C>T		intron	N/A	NP_071445.1
	NOD2	NM_001293557.2		c.2717+158C>T		intron	N/A	NP_001280486.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOD2	ENST00000647318.2	MANE Select	c.2717+158C>T		intron	N/A	ENSP00000495993.1
	NOD2	ENST00000300589.6	TSL:1	c.2798+158C>T		intron	N/A	ENSP00000300589.2
	NOD2	ENST00000534057.1	TSL:1	c.431+158C>T		intron	N/A	ENSP00000437246.1

Frequencies

GnomAD3 genomes AF: 0.109 AC: 16605 AN: 152048 Hom.: 1256 Cov.: 32

Gnomad AFR AF: 0.0314

Gnomad AMI AF: 0.157

Gnomad AMR AF: 0.112

Gnomad ASJ AF: 0.134

Gnomad EAS AF: 0.000770

Gnomad SAS AF: 0.0297

Gnomad FIN AF: 0.0590

Gnomad MID AF: 0.123

Gnomad NFE AF: 0.175

Gnomad OTH AF: 0.142

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.109 AC: 16599 AN: 152166 Hom.: 1256 Cov.: 32 AF XY: 0.103 AC XY: 7677 AN XY: 74390

African (AFR) AF: 0.0313 AC: 1300 AN: 41510

American (AMR) AF: 0.112 AC: 1706 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.134 AC: 466 AN: 3470

East Asian (EAS) AF: 0.000772 AC: 4 AN: 5184

South Asian (SAS) AF: 0.0295 AC: 142 AN: 4816

European-Finnish (FIN) AF: 0.0590 AC: 625 AN: 10590

Middle Eastern (MID) AF: 0.119 AC: 35 AN: 294

European-Non Finnish (NFE) AF: 0.175 AC: 11881 AN: 67988

Other (OTH) AF: 0.141 AC: 297 AN: 2108

Alfa AF: 0.152 Hom.: 6571

Bravo AF: 0.110

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:3 Benign:4 Other:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Blau syndrome Pathogenic:2 Uncertain:1

Feb 03, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

Laboratorio de Genética, Hospital Universitario Reina Sofía

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant has been reported in 84 caucassian patients (Borzutzky et al., 2009, Yao et al. 2011, Yao et al. 2015, Yao et al., 2012), all of them diagnosed of autoinflammatory disease with a clinical phenotype that resemble Blau’s syndrome. Based upon the literature and our own experience we classified this variant as likely pathogenic.

Apr 01, 2004

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

not provided Uncertain:1 Benign:1

Feb 01, 2020

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jun 09, 2025

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Identified with or without a second NOD2 variant in multiple patients with Yao syndrome, noted to be present at a higher frequency in cases versus controls. Per authors, approximately 30% of patients with Yao syndrome carry this variant with p.(R702W) (PMID: 26070941, 33394828); In silico analysis supports that this variant does not alter splicing; This variant is associated with the following publications: (PMID: 23584365, 29248579, 24682985, 26164256, 21914217, 28750667, 26070941, 33394828, 33692434, 23102769, 29471675, 39430755, 12577202, 34501225, 23824692, 24394805, 18758464, 15024686, 32127761, 26278503, 14765395, 19426395, 37928541, 26490195, 21079743, 26946932)

Yao syndrome Uncertain:1 Other:1

Apr 01, 2004

OMIM

Significance: risk factor

Review Status: no assertion criteria provided

Collection Method: literature only

Aug 18, 2020

Undiagnosed Diseases Network, NIH

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Autoinflammatory syndrome Benign:2

Nov 05, 2019

Breda Genetics srl

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is reported as risk factor for susceptibility to Crohn disease and susceptibility to Yao syndrome in ClinVar (Variation ID: 4697). It is also reported in ClinVar as pathogenic for Blau syndrome in one study for a patient with early-onset sarcoidosis and gastrointestinal granulomas (Borzutzky et al., 2010, PMID: 19467619), although in the article the authors define the variant only as polymorphism related to a susceptibility to Crohn disease. Furthermore, the variant is reported with an estimated allele frequency of 0.052 in 1000 Genomes Project and 0.1018 in gnomAD genomes, with homozygous individuals reported. We have also observed this variant in a large subset of samples without autoinflammatory syndromes at Breda Genetics. Based on the current evidence and high allele frequency, we interpret this variant as likely neutral in regard of pure mendelian inheritance for any form of genetic autoinflammatory syndrome.

Dec 12, 2016

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Regional enteritis;C5201146:Blau syndrome Benign:1

Jan 15, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Inflammatory bowel disease 1 Other:1

Apr 01, 2004

OMIM

Significance: risk factor

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.26
DANN	Benign	0.73
PhyloP100		-1.6
Mutation Taster		=100/0	polymorphism (auto)

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: rs5743289; hg19: chr16-50756774;