rs104895473

Positions:

• chr16-50711449-T-C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_001370466.1(NOD2):​c.1457T>C​(p.Met486Thr) variant causes a missense change. 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 Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NOD2 NM_001370466.1 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3 O:1
• Conservation: PhyloP100: 5.91

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 Pathogenic. Variant got 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.943
• PP5: Variant 16-50711449-T-C is Pathogenic according to our data. Variant chr16-50711449-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 97834.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-50711449-T-C is described in Lovd as [Pathogenic]. Variant chr16-50711449-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NOD2	NM_001370466.1	c.1457T>C	p.Met486Thr	missense_variant	4/12	ENST00000647318.2	NP_001357395.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NOD2	ENST00000647318.2	c.1457T>C	p.Met486Thr	missense_variant	4/12		NM_001370466.1	ENSP00000495993	P1
NOD2	ENST00000300589.6	c.1538T>C	p.Met513Thr	missense_variant	4/12	1		ENSP00000300589
NOD2	ENST00000641284.2	c.1457T>C	p.Met486Thr	missense_variant, NMD_transcript_variant	4/6			ENSP00000493088
NOD2	ENST00000646677.2	c.1457T>C	p.Met486Thr	missense_variant, NMD_transcript_variant	4/13			ENSP00000496533

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1461204 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 726918

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Blau syndrome Pathogenic:1 Other:1

not provided, no classification provided	literature only	Unité médicale des maladies autoinflammatoires, CHRU Montpellier	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	-	- -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Aug 01, 2024

NOD2: PM2, PM6, PS4:Moderate, PS3:Supporting, BP4 -

Regional enteritis;C5201146:Blau syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 30, 2020

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change leads to increased NF-kB activity (PMID: 15459013, 28130683, 25093298). This variant has been observed to be de novo in an individual affected with Blau syndrome (PMID: 25619344). In addition, it  has been observed in several individuals with a diagnosis or clinical features of Blau syndrome (PMID: 15459013, 28130683, 25416713, 28639104). ClinVar contains an entry for this variant (Variation ID: 97834). ClinVar contains an entry for this variant (Variation ID: 97834). This variant is not present in population databases (ExAC no frequency). This sequence change replaces methionine with threonine at codon 513 of the NOD2 protein (p.Met513Thr). The methionine residue is highly conserved and there is a moderate physicochemical difference between methionine and threonine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.54	.;D
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.81	T;T
M_CAP	Pathogenic	0.46	D
MetaRNN	Pathogenic	0.94	D;D
MetaSVM	Uncertain	-0.17	T
MutationAssessor	Pathogenic	3.1	.;M
MutationTaster	Benign	0.99	D
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-2.7	.;D
REVEL	Pathogenic	0.67
Sift	Uncertain	0.0040	.;D
Sift4G	Uncertain	0.018	.;D
Polyphen		0.73	P;P
Vest4		0.86
MutPred		0.90		.;Loss of helix (P = 0.0104);
MVP		0.93
MPC		0.19
ClinPred		0.95	D
GERP RS		5.1
Varity_R		0.55
gMVP		0.68

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: rs104895473; hg19: chr16-50745360;