rs104895460

Positions:

• chr16-50711316-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_001370466.1(NOD2):​c.1324C>T​(p.Leu442Phe) 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 (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: NOD2 NM_001370466.1 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: -0.0370

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 Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.887
• PP5: Variant 16-50711316-C-T is Pathogenic according to our data. Variant chr16-50711316-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 4695.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NOD2	NM_001370466.1	c.1324C>T	p.Leu442Phe	missense_variant	4/12	ENST00000647318.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NOD2	ENST00000647318.2	c.1324C>T	p.Leu442Phe	missense_variant	4/12		NM_001370466.1	P1
NOD2	ENST00000300589.6	c.1405C>T	p.Leu469Phe	missense_variant	4/12	1
NOD2	ENST00000641284.2	c.1324C>T	p.Leu442Phe	missense_variant, NMD_transcript_variant	4/6
NOD2	ENST00000646677.2	c.1324C>T	p.Leu442Phe	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: no assertion criteria provided

Submissions by phenotype

Blau syndrome Pathogenic:1 Other:1

not provided, no classification provided	literature only	Unité médicale des maladies autoinflammatoires, CHRU Montpellier	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 01, 2001	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.25	.;T
Eigen	Uncertain	0.31
Eigen_PC	Benign	0.22
FATHMM_MKL	Benign	0.46	N
LIST_S2	Benign	0.85	T;T
M_CAP	Pathogenic	0.33	D
MetaRNN	Pathogenic	0.89	D;D
MetaSVM	Uncertain	-0.11	T
MutationAssessor	Uncertain	2.6	.;M
MutationTaster	Benign	0.89	A
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-2.0	.;N
REVEL	Uncertain	0.40
Sift	Uncertain	0.0070	.;D
Sift4G	Uncertain	0.021	.;D
Polyphen		0.99	D;D
Vest4		0.72
MutPred		0.86		.;Loss of stability (P = 0.1189);
MVP		0.87
MPC		0.39
ClinPred		0.80	D
GERP RS		2.9
Varity_R		0.41
gMVP		0.58

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: rs104895460; hg19: chr16-50745227;