rs2076752

Positions:

• chr16-50697185-G-A
• chr16-50697185-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000300589.6(NOD2):​c.-59G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.258 in 1,429,068 control chromosomes in the GnomAD database, including 52,077 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.22 (4118 hom., cov: 33)
  • Exomes 𝑓: 0.26 (47959 hom.)
• Consequence: NOD2 ENST00000300589.6 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.998

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 16-50697185-G-A is Benign according to our data. Variant chr16-50697185-G-A is described in ClinVar as [Benign]. Clinvar id is 319419.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.285 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NOD2	NM_001370466.1	c.-8-2303G>A		intron_variant		ENST00000647318.2	NP_001357395.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NOD2	ENST00000647318.2	c.-8-2303G>A		intron_variant			NM_001370466.1	ENSP00000495993	P1

Frequencies

GnomAD3 genomes AF: 0.217 AC: 33059 AN: 152074 Hom.: 4117 Cov.: 33

Gnomad AFR AF: 0.139

Gnomad AMI AF: 0.330

Gnomad AMR AF: 0.201

Gnomad ASJ AF: 0.243

Gnomad EAS AF: 0.00943

Gnomad SAS AF: 0.149

Gnomad FIN AF: 0.198

Gnomad MID AF: 0.303

Gnomad NFE AF: 0.289

Gnomad OTH AF: 0.244

GnomAD4 exome AF: 0.263 AC: 335224 AN: 1276876 Hom.: 47959 Cov.: 19 AF XY: 0.261 AC XY: 166090 AN XY: 635932

Gnomad4 AFR exome AF: 0.136

Gnomad4 AMR exome AF: 0.149

Gnomad4 ASJ exome AF: 0.251

Gnomad4 EAS exome AF: 0.00437

Gnomad4 SAS exome AF: 0.175

Gnomad4 FIN exome AF: 0.199

Gnomad4 NFE exome AF: 0.291

Gnomad4 OTH exome AF: 0.241

GnomAD4 genome AF: 0.217 AC: 33078 AN: 152192 Hom.: 4118 Cov.: 33 AF XY: 0.212 AC XY: 15741 AN XY: 74404

Gnomad4 AFR AF: 0.139

Gnomad4 AMR AF: 0.200

Gnomad4 ASJ AF: 0.243

Gnomad4 EAS AF: 0.00945

Gnomad4 SAS AF: 0.150

Gnomad4 FIN AF: 0.198

Gnomad4 NFE AF: 0.289

Gnomad4 OTH AF: 0.244

Alfa AF: 0.262 Hom.: 3701

Bravo AF: 0.214

Asia WGS AF: 0.0870 AC: 310 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Nov 12, 2023

This variant is classified as Benign based on local population frequency. This variant was detected in 30% of patients studied by a panel of primary immunodeficiencies. Number of patients: 29. Only high quality variants are reported. -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Inflammatory bowel disease 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Blau syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.48
DANN	Benign	0.37

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: rs2076752; hg19: chr16-50731096;