16-50712049-G-A

Position:

• chr16-50712049-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS1

The NM_001370466.1(NOD2):​c.2057G>A​(p.Arg686His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000738 in 1,612,962 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00051 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00076 (1 hom.)
• Consequence: NOD2 NM_001370466.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:6 O:1
• Conservation: PhyloP100: 1.27

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.013140142).
• BP6: Variant 16-50712049-G-A is Benign according to our data. Variant chr16-50712049-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 97844.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-50712049-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000512 (78/152250) while in subpopulation NFE AF= 0.000764 (52/68044). AF 95% confidence interval is 0.000598. There are 0 homozygotes in gnomad4. There are 38 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NOD2	NM_001370466.1	c.2057G>A	p.Arg686His	missense_variant	4/12	ENST00000647318.2	NP_001357395.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NOD2	ENST00000647318.2	c.2057G>A	p.Arg686His	missense_variant	4/12		NM_001370466.1	ENSP00000495993.1
NOD2	ENST00000300589.6	c.2138G>A	p.Arg713His	missense_variant	4/12	1		ENSP00000300589.2
NOD2	ENST00000641284.2	n.2057G>A		non_coding_transcript_exon_variant	4/6			ENSP00000493088.1
NOD2	ENST00000646677.2	n.2057G>A		non_coding_transcript_exon_variant	4/13			ENSP00000496533.1

Frequencies

GnomAD3 genomes AF: 0.000512 AC: 78 AN: 152250 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00403

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000659

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000764

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000466 AC: 116 AN: 248772 Hom.: 2 AF XY: 0.000474 AC XY: 64 AN XY: 134936

Gnomad AFR exome AF: 0.000126

Gnomad AMR exome AF: 0.000434

Gnomad ASJ exome AF: 0.00270

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000235

Gnomad NFE exome AF: 0.000571

Gnomad OTH exome AF: 0.000492

GnomAD4 exome AF: 0.000762 AC: 1113 AN: 1460712 Hom.: 1 Cov.: 33 AF XY: 0.000709 AC XY: 515 AN XY: 726714

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.000291

Gnomad4 ASJ exome AF: 0.00237

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.000171

Gnomad4 NFE exome AF: 0.000895

Gnomad4 OTH exome AF: 0.000398

GnomAD4 genome AF: 0.000512 AC: 78 AN: 152250 Hom.: 0 Cov.: 33 AF XY: 0.000511 AC XY: 38 AN XY: 74388

Gnomad4 AFR AF: 0.0000482

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00403

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000659

Gnomad4 NFE AF: 0.000764

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000885 Hom.: 0

Bravo AF: 0.000465

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000228 AC: 1

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000338 AC: 41

EpiCase AF: 0.000654

EpiControl AF: 0.000711

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1 Benign:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	NOD2: BP4, BS1 -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 20, 2023	- -

Blau syndrome Benign:1 Other:1

not provided, no classification provided	literature only	Unité médicale des maladies autoinflammatoires, CHRU Montpellier	-	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

NOD2-related disorder Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 04, 2024

The NOD2 c.2138G>A variant is predicted to result in the amino acid substitution p.Arg713His. This variant has been reported in individuals with inflammatory bowel disease (Schnitzler et al. 2006. PubMed ID: 16485124; Andreoletti et al. 2017. PubMed ID: 28422189) and orofacial granulomatosis (Mentzer et al. 2016. PubMed ID: 27306066). This variant was also identified in an control population (Andreoletti et al. 2017. PubMed ID: 28422189) and is reported in 0.28% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Regional enteritis;C5201146:Blau syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Autoinflammatory syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Apr 07, 2021

- -

Inflammatory bowel disease 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.16	.;T
Eigen	Benign	-0.15
Eigen_PC	Benign	0.019
FATHMM_MKL	Benign	0.45	N
LIST_S2	Benign	0.78	T;T
M_CAP	Uncertain	0.098	D
MetaRNN	Benign	0.013	T;T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	1.9	.;M
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.2	.;N
REVEL	Benign	0.057
Sift	Benign	0.35	.;T
Sift4G	Benign	0.18	.;T
Polyphen		0.10	B;B
Vest4		0.17
MVP		0.86
MPC		0.12
ClinPred		0.027	T
GERP RS		4.8
Varity_R		0.039
gMVP		0.26

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: rs104895483; hg19: chr16-50745960;