rs4785225

Positions:

• chr16-50712635-C-G
• chr16-50712635-C-T

Variant summary

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

The NM_001370466.1(NOD2):​c.2381+262C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.602 in 551,014 control chromosomes in the GnomAD database, including 105,205 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.61 (28758 hom., cov: 32)
  • Exomes 𝑓: 0.60 (76447 hom.)
• Consequence: NOD2 NM_001370466.1 intron
• Scores: Splicing: ADA: 0.00004300
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.223

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=-0.88).
• BP6: Variant 16-50712635-C-G is Benign according to our data. Variant chr16-50712635-C-G is described in ClinVar as [Benign]. Clinvar id is 1237708.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.665 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NOD2	NM_001370466.1	c.2381+262C>G		intron_variant		ENST00000647318.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NOD2	ENST00000647318.2	c.2381+262C>G		intron_variant			NM_001370466.1	P1

Frequencies

GnomAD3 genomes AF: 0.605 AC: 91968 AN: 151922 Hom.: 28745 Cov.: 32

Gnomad AFR AF: 0.586

Gnomad AMI AF: 0.745

Gnomad AMR AF: 0.564

Gnomad ASJ AF: 0.775

Gnomad EAS AF: 0.193

Gnomad SAS AF: 0.347

Gnomad FIN AF: 0.569

Gnomad MID AF: 0.658

Gnomad NFE AF: 0.670

Gnomad OTH AF: 0.623

GnomAD4 exome AF: 0.600 AC: 239544 AN: 398974 Hom.: 76447 Cov.: 3 AF XY: 0.589 AC XY: 123154 AN XY: 208990

Gnomad4 AFR exome AF: 0.596

Gnomad4 AMR exome AF: 0.504

Gnomad4 ASJ exome AF: 0.786

Gnomad4 EAS exome AF: 0.226

Gnomad4 SAS exome AF: 0.395

Gnomad4 FIN exome AF: 0.577

Gnomad4 NFE exome AF: 0.677

Gnomad4 OTH exome AF: 0.613

GnomAD4 genome AF: 0.605 AC: 92025 AN: 152040 Hom.: 28758 Cov.: 32 AF XY: 0.596 AC XY: 44259 AN XY: 74312

Gnomad4 AFR AF: 0.586

Gnomad4 AMR AF: 0.564

Gnomad4 ASJ AF: 0.775

Gnomad4 EAS AF: 0.193

Gnomad4 SAS AF: 0.348

Gnomad4 FIN AF: 0.569

Gnomad4 NFE AF: 0.670

Gnomad4 OTH AF: 0.619

Alfa AF: 0.509 Hom.: 1429

Bravo AF: 0.605

Asia WGS AF: 0.294 AC: 1028 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 10, 2018	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Jan 24, 2024

This variant is classified as Benign based on local population frequency. This variant was detected in 82% of patients studied by a panel of primary immunodeficiencies. Number of patients: 78. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	5.1
DANN	Benign	0.49

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000043
dbscSNV1_RF	Benign	0.12
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: rs4785225; hg19: chr16-50746546;