16-50697185-G-A

Variant names:

• chr16-50697185-G-A
• rs2076752
• ENST00000532206.1:n.46G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001370466.1(NOD2):​c.-8-2303G>A variant causes a intron 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 NM_001370466.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.998
• Publications: 14 publications found

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 Gene-Disease associations (from GenCC):

• Blau syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet, Genomics England PanelApp, G2P, Illumina, Labcorp Genetics (formerly Invitae)
• inflammatory bowel disease 1

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
NOD2	NM_001370466.1	c.-8-2303G>A		intron_variant	Intron 1 of 11	ENST00000647318.2	NP_001357395.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOD2	ENST00000647318.2	c.-8-2303G>A		intron_variant	Intron 1 of 11		NM_001370466.1	ENSP00000495993.1

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

African (AFR) AF: 0.136 AC: 3972 AN: 29166

American (AMR) AF: 0.149 AC: 5298 AN: 35534

Ashkenazi Jewish (ASJ) AF: 0.251 AC: 6134 AN: 24428

East Asian (EAS) AF: 0.00437 AC: 154 AN: 35266

South Asian (SAS) AF: 0.175 AC: 13422 AN: 76758

European-Finnish (FIN) AF: 0.199 AC: 9705 AN: 48832

Middle Eastern (MID) AF: 0.284 AC: 1244 AN: 4380

European-Non Finnish (NFE) AF: 0.291 AC: 282303 AN: 968580

Other (OTH) AF: 0.241 AC: 12992 AN: 53932

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

African (AFR) AF: 0.139 AC: 5760 AN: 41534

American (AMR) AF: 0.200 AC: 3064 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.243 AC: 842 AN: 3470

East Asian (EAS) AF: 0.00945 AC: 49 AN: 5186

South Asian (SAS) AF: 0.150 AC: 726 AN: 4824

European-Finnish (FIN) AF: 0.198 AC: 2097 AN: 10580

Middle Eastern (MID) AF: 0.298 AC: 87 AN: 292

European-Non Finnish (NFE) AF: 0.289 AC: 19638 AN: 67986

Other (OTH) AF: 0.244 AC: 515 AN: 2110

Alfa AF: 0.255 Hom.: 5030

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

Nov 12, 2023

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Inflammatory bowel disease 1 Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
PhyloP100		-1.0
PromoterAI		-0.019	Neutral
Mutation Taster		=300/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2076752; hg19: chr16-50731096;