16-50710912-G-T

Variant names:

• chr16-50710912-G-T
• NM_001370466.1:c.920G>T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2 PM5 PP3_Strong PP5_Moderate

The NM_001370466.1(NOD2):​c.920G>T​(p.Arg307Leu) 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. R307Q) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: NOD2 NM_001370466.1 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 4.63

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 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-50710912-G-A is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.988
• PP5: Variant 16-50710912-G-T is Pathogenic according to our data. Variant chr16-50710912-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2921258.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOD2	NM_001370466.1	c.920G>T	p.Arg307Leu	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.920G>T	p.Arg307Leu	missense_variant	Exon 4 of 12		NM_001370466.1	ENSP00000495993.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 39

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Nov 22, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The NOD2 c.1001G>T; p.Arg334Leu variant is reported in the literature in an individual with Blau syndrome (Li 2017). This variant is absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. Computational analyses predict that this variant is deleterious (REVEL: 0.772). Additionally, other variants at this codon (c.1001G>A, p.Arg334Gln; c.1000C>T, p.Arg334Trp) have been reported in individuals with Blau syndrome and are considered pathogenic (Li 2017, Miceli-Richard 2001, Zhong 2022). Based on available information, the p.Arg334Leu variant is considered to be likely pathogenic. References: Li C et al. Gene mutations and clinical phenotypes in Chinese children with Blau syndrome. Sci China Life Sci. 2017 Jul;60(7):758-762. PMID: 28639104. Miceli-Richard C et al. CARD15 mutations in Blau syndrome. Nat Genet. 2001 Sep;29(1):19-20. PMID: 11528384. Zhong Z et al. Genetic and Clinical Features of Blau Syndrome among Chinese Patients with Uveitis. Ophthalmology. 2022 Jul;129(7):821-828. PMID: 35314268. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.68
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.64	.;D
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.92	D;D
M_CAP	Pathogenic	0.63	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Uncertain	0.58	D
MutationAssessor	Pathogenic	3.9	.;H
PrimateAI	Uncertain	0.49	T
PROVEAN	Pathogenic	-5.9	.;D
REVEL	Pathogenic	0.77
Sift	Uncertain	0.0030	.;D
Sift4G	Pathogenic	0.0	.;D
Polyphen		1.0	D;D
Vest4		0.91
MutPred		0.92		.;Gain of catalytic residue at Q335 (P = 0.1676);
MVP		0.92
MPC		0.55
ClinPred		1.0	D
GERP RS		4.8
Varity_R		0.85
gMVP		0.85

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-50744823;