16-50711398-A-T

Variant names:

• chr16-50711398-A-T
• rs104895472
• NM_001370466.1:c.1406A>T

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM2 PP3_Moderate PP5

The NM_001370466.1(NOD2):​c.1406A>T​(p.His469Leu) 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H469R) has been classified as Uncertain significance.

• 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: 2.98
• Publications: 8 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: Likely_pathogenic. The variant received 7 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 13 uncertain in NM_001370466.1
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.937
• PP5: Variant 16-50711398-A-T is Pathogenic according to our data. Variant chr16-50711398-A-T is described in ClinVar as Pathogenic. ClinVar VariationId is 4698.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOD2	NM_001370466.1	c.1406A>T	p.His469Leu	missense_variant	Exon 4 of 12	ENST00000647318.2	NP_001357395.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOD2	ENST00000647318.2	c.1406A>T	p.His469Leu	missense_variant	Exon 4 of 12		NM_001370466.1	ENSP00000495993.1
NOD2	ENST00000300589.6	c.1487A>T	p.His496Leu	missense_variant	Exon 4 of 12	1		ENSP00000300589.2
NOD2	ENST00000641284.2	n.1406A>T		non_coding_transcript_exon_variant	Exon 4 of 6			ENSP00000493088.1
NOD2	ENST00000646677.2	n.1406A>T		non_coding_transcript_exon_variant	Exon 4 of 13			ENSP00000496533.1

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

Feb 01, 2005

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

-

Unité médicale des maladies autoinflammatoires, CHRU Montpellier

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Uncertain	24
DANN	Benign	0.97
DEOGEN2	Benign	0.17	.;T
Eigen	Benign	0.16
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.82	T;T
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.94	D;D
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	0.38	.;N
PhyloP100		3.0
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-2.3	.;N
REVEL	Uncertain	0.42
Sift	Benign	0.11	.;T
Sift4G	Uncertain	0.0060	.;D
Polyphen		0.99	D;D
Vest4		0.68
MutPred		0.84		.;Gain of stability (P = 0.0061);
MVP		0.88
MPC		0.50
ClinPred		0.87	D
GERP RS		5.0
Varity_R		0.20
gMVP		0.67
Mutation Taster		=62/38	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs104895472; hg19: chr16-50745309;