rs104895473

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M486K) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

NOD2
NM_001370466.1 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3O:1

Conservation

PhyloP100: 5.91

Publications

19 publications found

Variant links:

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)

NOD2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 97834.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOD2	NM_001370466.1 link	c.1457T>C	p.Met486Thr	missense_variant	Exon 4 of 12	ENST00000647318.2	NP_001357395.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
NOD2	ENST00000647318.2 link	c.1457T>C	p.Met486Thr	missense_variant	Exon 4 of 12		NM_001370466.1	ENSP00000495993.1	Q9HC29-2
NOD2	ENST00000300589.6 link	c.1538T>C	p.Met513Thr	missense_variant	Exon 4 of 12	1		ENSP00000300589.2	Q9HC29-1
NOD2	ENST00000641284.2 link	n.1457T>C		non_coding_transcript_exon_variant	Exon 4 of 6			ENSP00000493088.1	A0A286YF65
NOD2	ENST00000646677.2 link	n.1457T>C		non_coding_transcript_exon_variant	Exon 4 of 13			ENSP00000496533.1	A0A286YF65

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1461204

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726918

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52772

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111982

Other (OTH)

AF:

0.00

AC:

AN:

60390

GnomAD4 genome

Cov.:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Blau syndrome

Pathogenic:1Other:1

Unité médicale des maladies autoinflammatoires, CHRU Montpellier

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Pathogenic:1

Aug 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Regional enteritis;C5201146:Blau syndrome

Pathogenic:1

Aug 30, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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:¬¨‚Ä†15459013,¬¨‚Ä†28130683,¬¨‚Ä†25093298). This variant has been observed to be de novo in an individual affected with Blau syndrome (PMID:¬¨‚Ä†25619344). In addition, it¬¨‚Ä† has been observed in several individuals with a diagnosis or clinical features of Blau syndrome (PMID:¬¨‚Ä†15459013,¬¨‚Ä†28130683,¬¨‚Ä†25416713,¬¨‚Ä†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

BayesDel_noAF

Pathogenic

0.25

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.54

.;D

Eigen

Uncertain

0.43

Eigen_PC

Uncertain

0.46

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.81

T;T

M_CAP

Pathogenic

0.46

MetaRNN

Pathogenic

0.94

D;D

MetaSVM

Uncertain

-0.17

MutationAssessor

Pathogenic

3.1

.;M

PhyloP100

5.9

PrimateAI

Uncertain

0.55

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

GERP RS

5.1

Varity_R

0.55

gMVP

0.68

Mutation Taster

=21/79

disease causing (ClinVar)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over