16-50722863-C-T

Variant names:

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

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong 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:1 U:2 B:5 O:2
• Conservation: PhyloP100: -1.58

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.172 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOD2	NM_001370466.1	c.2717+158C>T		intron_variant	Intron 8 of 11	ENST00000647318.2	NP_001357395.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOD2	ENST00000647318.2	c.2717+158C>T		intron_variant	Intron 8 of 11		NM_001370466.1	ENSP00000495993.1

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

Gnomad4 AFR AF: 0.0313

Gnomad4 AMR AF: 0.112

Gnomad4 ASJ AF: 0.134

Gnomad4 EAS AF: 0.000772

Gnomad4 SAS AF: 0.0295

Gnomad4 FIN AF: 0.0590

Gnomad4 NFE AF: 0.175

Gnomad4 OTH AF: 0.141

Alfa AF: 0.157 Hom.: 3191

Bravo AF: 0.110

ClinVar

Significance: Conflicting classifications of pathogenicity

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

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Blau syndrome Pathogenic:1 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

- -

Apr 01, 2004

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Yao syndrome Uncertain:1 Other:1

Aug 18, 2020

Undiagnosed Diseases Network, NIH

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 01, 2004

OMIM

Significance: risk factor

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Benign:2

Feb 01, 2020

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 24, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 26164256, 29248579, 28750667, 19426395, 21914217, 23584365, 23102769, 12577202, 24682985) -

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 v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.26
DANN	Benign	0.73

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: rs5743289; hg19: chr16-50756774;