16-50710842-C-T

Variant names:

• chr16-50710842-C-T
• rs104895427
• NM_001370466.1:c.850C>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.850C>T​(p.Arg284Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000661 in 1,614,058 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R284Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00058 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00067 (6 hom.)
• Consequence: NOD2 NM_001370466.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:4 O:1
• Conservation: PhyloP100: 2.88
• Publications: 31 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=0.05836901).
• BP6: Variant 16-50710842-C-T is Benign according to our data. Variant chr16-50710842-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 97885.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000584 (89/152286) while in subpopulation EAS AF = 0.00309 (16/5178). AF 95% confidence interval is 0.00194. There are 0 homozygotes in GnomAd4. There are 45 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 89 AD,Unknown gene.

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.850C>T	p.Arg284Trp	missense	Exon 4 of 12	NP_001357395.1
	NOD2	NM_022162.3		c.931C>T	p.Arg311Trp	missense	Exon 4 of 12	NP_071445.1
	NOD2	NM_001293557.2		c.850C>T	p.Arg284Trp	missense	Exon 3 of 11	NP_001280486.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOD2	ENST00000647318.2	MANE Select	c.850C>T	p.Arg284Trp	missense	Exon 4 of 12	ENSP00000495993.1
	NOD2	ENST00000300589.6	TSL:1	c.931C>T	p.Arg311Trp	missense	Exon 4 of 12	ENSP00000300589.2
	NOD2	ENST00000526417.6	TSL:1	n.991C>T		non_coding_transcript_exon	Exon 5 of 5

Frequencies

GnomAD3 genomes AF: 0.000585 AC: 89 AN: 152168 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00987

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.00308

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000617

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000590 AC: 148 AN: 250870 AF XY: 0.000567

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000926

Gnomad ASJ exome AF: 0.000397

Gnomad EAS exome AF: 0.00163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000644

Gnomad OTH exome AF: 0.000653

GnomAD4 exome AF: 0.000669 AC: 978 AN: 1461772 Hom.: 6 Cov.: 39 AF XY: 0.000639 AC XY: 465 AN XY: 727186

African (AFR) AF: 0.0000896 AC: 3 AN: 33478

American (AMR) AF: 0.000939 AC: 42 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.000383 AC: 10 AN: 26134

East Asian (EAS) AF: 0.00544 AC: 216 AN: 39698

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53318

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.000593 AC: 659 AN: 1112004

Other (OTH) AF: 0.000695 AC: 42 AN: 60396

GnomAD4 genome AF: 0.000584 AC: 89 AN: 152286 Hom.: 0 Cov.: 33 AF XY: 0.000604 AC XY: 45 AN XY: 74448

African (AFR) AF: 0.0000962 AC: 4 AN: 41570

American (AMR) AF: 0.00105 AC: 16 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.000577 AC: 2 AN: 3466

East Asian (EAS) AF: 0.00309 AC: 16 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

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

European-Non Finnish (NFE) AF: 0.000618 AC: 42 AN: 68016

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

Alfa AF: 0.000633 Hom.: 0

Bravo AF: 0.000586

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.000511 AC: 62

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000600

EpiControl AF: 0.000889

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:4 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Jun 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NOD2: BS1

Oct 27, 2014

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Inflammatory bowel disease 1 Uncertain:1 Benign:1

Baylor-Hopkins Center for Mendelian Genomics, Johns Hopkins University School of Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

Blau syndrome Benign:1 Other:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

Unité médicale des maladies autoinflammatoires, CHRU Montpellier

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Yao syndrome;C5201146:Blau syndrome;CN260071:Inflammatory bowel disease 1 Uncertain:1

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NOD2 NM_022162.2 exon 4 p.Arg311Trp (c.931C>T):This variant has been reported in the literature in at least 3 individuals with autoimmune related disease (e.g. Crohn's disease, ulcerative colitis, Behcet's disease), with most authors suggesting this variant may act as a risk allele (Lesage 2002 PMID:11875755, Rivas 2011 PMID:21983784, Burillo-Sanz 2017 PMID:28814775). This variant is present in 0.1% (30/18870) of East Asian alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs104895427). This variant is present in ClinVar (Variation ID:97885). Evolutionary conservation and computational predictive tools for this variant are unclear. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.

NOD2-related disorder Uncertain:1

Sep 09, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The NOD2 c.931C>T variant is predicted to result in the amino acid substitution p.Arg311Trp. This variant has been identified in patients with Cohn’s disease and ulcerative colitis (Lesage et al. 2002. PubMed ID: 11875755; Rivas et al. 2011. PubMed ID: 21983784). Additional functional studies that analyzed basal activity and the ability to respond to PGN determined the p.Arg311Trp variant was indistinguishable from wildtype samples (Chamaillard et al. 2003. PubMed ID: 12626759). In addition, this variant has also been identified in patients with aggressive periodontitis and Behcet’s disease (Burillo-Sanz et al. 2017. PubMed ID: 28814775; Sudo et al. 2017. PubMed ID: 28682159). This variant is reported in 0.16% of alleles in individuals of East Asian descent in gnomAD and is reported in the homozygous state in one individual of Latino descent, which may be too common to be causative of disease. This variant has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from likely benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/97885/). 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

Dec 31, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.13
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.42	T
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.83	T
M_CAP	Pathogenic	0.47	D
MetaRNN	Benign	0.058	T
MetaSVM	Uncertain	-0.083	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		2.9
PrimateAI	Benign	0.26	T
PROVEAN	Pathogenic	-4.6	D
REVEL	Uncertain	0.63
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.34
MVP		0.94
MPC		0.50
ClinPred		0.094	T
GERP RS		5.6
Varity_R		0.32
gMVP		0.74
Mutation Taster		=93/7	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs104895427; hg19: chr16-50744753; COSMIC: COSV56049177; COSMIC: COSV56049177;