rs2297512

chr17-27765529-G-Achr17-27765529-G-T

Variant summary

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

The NM_000625.4(NOS2):c.2428+6C>T variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.633 in 1,588,414 control chromosomes in the GnomAD database, including 322,144 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.68 (35219 hom., cov: 33)
  • Exomes 𝑓: 0.63 (286925 hom.)
• Consequence: NOS2 NM_000625.4 splice_donor_region, intron
• Scores: Splicing: ADA: 0.0001130
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.158

Genes affected

NOS2 (HGNC:7873): (nitric oxide synthase 2) Nitric oxide is a reactive free radical which acts as a biologic mediator in several processes, including neurotransmission and antimicrobial and antitumoral activities. This gene encodes a nitric oxide synthase which is expressed in liver and is inducible by a combination of lipopolysaccharide and certain cytokines. Three related pseudogenes are located within the Smith-Magenis syndrome region on chromosome 17. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 17-27765529-G-A is Benign according to our data. Variant chr17-27765529-G-A is described in ClinVar as [Benign]. Clinvar id is 2687956.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.812 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NOS2	NM_000625.4	c.2428+6C>T		splice_donor_region_variant, intron_variant		ENST00000313735.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NOS2	ENST00000313735.11	c.2428+6C>T		splice_donor_region_variant, intron_variant		1	NM_000625.4	P2

Frequencies

GnomAD3 genomes AF: 0.675 AC: 102615 AN: 152026 Hom.: 35165 Cov.: 33

Gnomad AFR AF: 0.780

Gnomad AMI AF: 0.763

Gnomad AMR AF: 0.662

Gnomad ASJ AF: 0.686

Gnomad EAS AF: 0.692

Gnomad SAS AF: 0.833

Gnomad FIN AF: 0.591

Gnomad MID AF: 0.801

Gnomad NFE AF: 0.612

Gnomad OTH AF: 0.689

GnomAD3 exomes AF: 0.648 AC: 148417 AN: 228906 Hom.: 49108 AF XY: 0.655 AC XY: 81427 AN XY: 124312

Gnomad AFR exome AF: 0.783

Gnomad AMR exome AF: 0.609

Gnomad ASJ exome AF: 0.666

Gnomad EAS exome AF: 0.687

Gnomad SAS exome AF: 0.826

Gnomad FIN exome AF: 0.578

Gnomad NFE exome AF: 0.601

Gnomad OTH exome AF: 0.647

GnomAD4 exome AF: 0.628 AC: 902060 AN: 1436270 Hom.: 286925 Cov.: 38 AF XY: 0.634 AC XY: 451402 AN XY: 712348

Gnomad4 AFR exome AF: 0.792

Gnomad4 AMR exome AF: 0.614

Gnomad4 ASJ exome AF: 0.680

Gnomad4 EAS exome AF: 0.730

Gnomad4 SAS exome AF: 0.826

Gnomad4 FIN exome AF: 0.582

Gnomad4 NFE exome AF: 0.604

Gnomad4 OTH exome AF: 0.652

GnomAD4 genome AF: 0.675 AC: 102730 AN: 152144 Hom.: 35219 Cov.: 33 AF XY: 0.678 AC XY: 50404 AN XY: 74366

Gnomad4 AFR AF: 0.780

Gnomad4 AMR AF: 0.663

Gnomad4 ASJ AF: 0.686

Gnomad4 EAS AF: 0.692

Gnomad4 SAS AF: 0.834

Gnomad4 FIN AF: 0.591

Gnomad4 NFE AF: 0.612

Gnomad4 OTH AF: 0.690

Alfa AF: 0.650 Hom.: 9432

Bravo AF: 0.679

Asia WGS AF: 0.773 AC: 2691 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

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

Jan 24, 2024

This variant is classified as Benign based on local population frequency. This variant was detected in 87% of patients studied by a panel of primary immunodeficiencies. Number of patients: 83. Only high quality variants are reported. -

NOS2-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 17, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
Cadd	Benign	8.7
Dann	Benign	0.48

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00011
dbscSNV1_RF	Benign	0.0020
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: rs2297512; hg19: chr17-26092555;