16-50700058-A-G

Variant names:

• chr16-50700058-A-G
• rs2111235
• NM_001370466.1:c.459+104A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001370466.1(NOD2):​c.459+104A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.648 in 1,093,490 control chromosomes in the GnomAD database, including 236,081 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.65 (32992 hom., cov: 32)
  • Exomes 𝑓: 0.65 (203089 hom.)
• Consequence: NOD2 NM_001370466.1 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.15
• Publications: 18 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 16-50700058-A-G is Benign according to our data. Variant chr16-50700058-A-G is described in ClinVar as Benign. ClinVar VariationId is 2688412.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.691 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001370466.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOD2	NM_001370466.1	MANE Select	c.459+104A>G		intron	N/A	NP_001357395.1
	NOD2	NM_022162.3		c.540+104A>G		intron	N/A	NP_071445.1
	NOD2	NM_001293557.2		c.459+104A>G		intron	N/A	NP_001280486.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOD2	ENST00000647318.2	MANE Select	c.459+104A>G		intron	N/A	ENSP00000495993.1
	NOD2	ENST00000300589.6	TSL:1	c.540+104A>G		intron	N/A	ENSP00000300589.2
	NOD2	ENST00000527070.5	TSL:1	c.459+104A>G		intron	N/A	ENSP00000435149.2

Frequencies

GnomAD3 genomes AF: 0.651 AC: 98978 AN: 151980 Hom.: 32987 Cov.: 32

Gnomad AFR AF: 0.665

Gnomad AMI AF: 0.748

Gnomad AMR AF: 0.586

Gnomad ASJ AF: 0.791

Gnomad EAS AF: 0.250

Gnomad SAS AF: 0.469

Gnomad FIN AF: 0.624

Gnomad MID AF: 0.684

Gnomad NFE AF: 0.697

Gnomad OTH AF: 0.662

GnomAD4 exome AF: 0.647 AC: 609201 AN: 941392 Hom.: 203089 AF XY: 0.643 AC XY: 308777 AN XY: 480562

African (AFR) AF: 0.665 AC: 15543 AN: 23364

American (AMR) AF: 0.474 AC: 16649 AN: 35154

Ashkenazi Jewish (ASJ) AF: 0.799 AC: 17557 AN: 21966

East Asian (EAS) AF: 0.274 AC: 9321 AN: 34048

South Asian (SAS) AF: 0.500 AC: 35466 AN: 70870

European-Finnish (FIN) AF: 0.623 AC: 21910 AN: 35158

Middle Eastern (MID) AF: 0.690 AC: 2570 AN: 3722

European-Non Finnish (NFE) AF: 0.686 AC: 462596 AN: 673870

Other (OTH) AF: 0.638 AC: 27589 AN: 43240

GnomAD4 genome AF: 0.651 AC: 99032 AN: 152098 Hom.: 32992 Cov.: 32 AF XY: 0.642 AC XY: 47734 AN XY: 74336

African (AFR) AF: 0.664 AC: 27560 AN: 41478

American (AMR) AF: 0.586 AC: 8949 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.791 AC: 2745 AN: 3470

East Asian (EAS) AF: 0.251 AC: 1295 AN: 5162

South Asian (SAS) AF: 0.469 AC: 2261 AN: 4824

European-Finnish (FIN) AF: 0.624 AC: 6592 AN: 10570

Middle Eastern (MID) AF: 0.680 AC: 200 AN: 294

European-Non Finnish (NFE) AF: 0.697 AC: 47359 AN: 67994

Other (OTH) AF: 0.658 AC: 1389 AN: 2112

Alfa AF: 0.587 Hom.: 3982

Bravo AF: 0.648

Asia WGS AF: 0.387 AC: 1349 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Jan 24, 2024

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 51% of patients studied by a panel of primary immunodeficiencies. Number of patients: 45. Only high quality variants are reported.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.0020
DANN	Benign	0.53
PhyloP100		-1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs2111235; hg19: chr16-50733969; COSMIC: COSV56050565; COSMIC: COSV56050565;