rs104895475

chr16-50711921-C-Achr16-50711921-C-Gchr16-50711921-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Moderate PP5_Moderate

The NM_001370466.1(NOD2):c.1929C>A(p.Asn643Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar. Synonymous variant affecting the same amino acid position (i.e. N643N) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: NOD2 NM_001370466.1 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1 O:1
• Conservation: PhyloP100: 0.784

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.903
• PP5: Variant 16-50711921-C-A is Pathogenic according to our data. Variant chr16-50711921-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 97842.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NOD2	NM_001370466.1	c.1929C>A	p.Asn643Lys	missense_variant	4/12	ENST00000647318.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NOD2	ENST00000647318.2	c.1929C>A	p.Asn643Lys	missense_variant	4/12		NM_001370466.1	P1
NOD2	ENST00000300589.6	c.2010C>A	p.Asn670Lys	missense_variant	4/12	1
NOD2	ENST00000641284.2	c.1929C>A	p.Asn643Lys	missense_variant, NMD_transcript_variant	4/6
NOD2	ENST00000646677.2	c.1929C>A	p.Asn643Lys	missense_variant, NMD_transcript_variant	4/13

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Regional enteritis;C5201146:Blau syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jul 17, 2023

This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 670 of the NOD2 protein (p.Asn670Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Blau syndrome or early onset sarcoidosis (PMID: 15459013, 20039400, 32647028). ClinVar contains an entry for this variant (Variation ID: 97842). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt NOD2 protein function. Experimental studies have shown that this missense change affects NOD2 function (PMID: 15459013, 20039400, 25093298). For these reasons, this variant has been classified as Pathogenic. -

Blau syndrome Other:1

not provided, no classification provided

literature only

Unité médicale des maladies autoinflammatoires, CHRU Montpellier

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Uncertain	0.025	T
BayesDel_noAF	Benign	-0.20
Cadd	Benign	21
Dann	Uncertain	1.0
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.88	D;D
M_CAP	Pathogenic	0.54	D
MetaRNN	Pathogenic	0.90	D;D
MetaSVM	Benign	-0.31	T
MutationTaster	Benign	0.99	D
PrimateAI	Uncertain	0.61	T
Polyphen		1.0	D;D
Vest4		0.75
MutPred		0.83		.;Gain of ubiquitination at N670 (P = 0.0177);
MVP		0.90
MPC		0.52
ClinPred		0.91	D
GERP RS		2.6
Varity_R		0.21
gMVP		0.65

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: rs104895475; hg19: chr16-50745832;