16-50710623-A-G

Position:

• chr16-50710623-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001370466.1(NOD2):​c.631A>G​(p.Ser211Gly) variant causes a missense change. The variant allele was found at a frequency of 0.0000329 in 152,188 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S211C) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.000033 (0 hom., cov: 32)
• Consequence: NOD2 NM_001370466.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.93

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2682542).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NOD2	NM_001370466.1	c.631A>G	p.Ser211Gly	missense_variant	4/12	ENST00000647318.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NOD2	ENST00000647318.2	c.631A>G	p.Ser211Gly	missense_variant	4/12		NM_001370466.1	P1

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152188 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152188 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74344

Gnomad4 AFR AF: 0.000121

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000529

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Regional enteritis;C5201146:Blau syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jun 20, 2022

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. 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. ClinVar contains an entry for this variant (Variation ID: 961890). This variant has not been reported in the literature in individuals affected with NOD2-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.02%). This sequence change replaces serine, which is neutral and polar, with glycine, which is neutral and non-polar, at codon 238 of the NOD2 protein (p.Ser238Gly). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Uncertain	0.026	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	22
DANN	Benign	0.94
Eigen	Benign	-0.017
Eigen_PC	Benign	0.065
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.79	T;T
M_CAP	Benign	0.081	D
MetaRNN	Benign	0.27	T;T
MetaSVM	Benign	-0.74	T
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.48	T
Polyphen		0.040	B;P
Vest4		0.36
MutPred		0.32		.;Gain of helix (P = 0.0225);
MVP		0.89
MPC		0.094
ClinPred		0.84	D
GERP RS		5.3
Varity_R		0.10
gMVP		0.56

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: rs1001861018; hg19: chr16-50744534;