16-50729838-C-T

Position:

• chr16-50729838-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001370466.1(NOD2):​c.2906C>T​(p.Thr969Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,460,650 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: NOD2 NM_001370466.1 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.31

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]

CYLD-AS1 (HGNC:55352): (CYLD antisense RNA 1)

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NOD2	NM_001370466.1	c.2906C>T	p.Thr969Ile	missense_variant	11/12	ENST00000647318.2	NP_001357395.1
CYLD-AS1	NR_184279.1	n.523+5G>A		splice_donor_5th_base_variant, intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NOD2	ENST00000647318.2	c.2906C>T	p.Thr969Ile	missense_variant	11/12		NM_001370466.1	ENSP00000495993	P1
CYLD-AS1	ENST00000563315.2	n.1124+5G>A		splice_donor_5th_base_variant, intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460650 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726652

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Blau syndrome;CN260071:Inflammatory bowel disease 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

New York Genome Center

Jun 03, 2021

The inherited heterozygous c.2987C>T (p.Thr996Ile) missense variant identified in the NOD2 gene has not been reported in affected individuals in the literature. The variant is absent from gnomAD(v3) database suggesting it is not a common benign variant in the populations represented in thatdatabase. In silico tools provide conflicting predictions about potential pathogenicity of this variant (CADD score = 23.4, REVEL score = 0.295). Based on the available evidence, the inherited heterozygous c.2987C>T (p.Thr996Ile) missense variant identified in the NOD2 gene is reported as a variantof uncertain significance. -

Regional enteritis;C5201146:Blau syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 26, 2020

This sequence change replaces threonine with isoleucine at codon 996 of the NOD2 protein (p.Thr996Ile). The threonine residue is moderately conserved and there is a moderate physicochemical difference between threonine and isoleucine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with NOD2-related conditions. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt NOD2 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.74
BayesDel_addAF	Uncertain	0.019	T
BayesDel_noAF	Benign	-0.21
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	.;T
Eigen	Uncertain	0.22
Eigen_PC	Benign	0.094
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.80	T;T
M_CAP	Benign	0.043	D
MetaRNN	Uncertain	0.49	T;T
MetaSVM	Benign	-0.48	T
MutationAssessor	Pathogenic	3.5	.;M
MutationTaster	Benign	1.0	N
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-4.3	.;D
REVEL	Uncertain	0.29
Sift	Uncertain	0.0010	.;D
Sift4G	Uncertain	0.014	.;D
Polyphen		0.99	.;D
Vest4		0.69
MutPred		0.61		.;Loss of loop (P = 0.2237);
MVP		0.93
MPC		0.49
ClinPred		0.99	D
GERP RS		3.6
Varity_R		0.40
gMVP		0.62

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: rs1567407613; hg19: chr16-50763749;