17-27765605-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000625.4(NOS2):c.2358T>C(p.Gly786=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.635 in 1,612,444 control chromosomes in the GnomAD database, including 329,856 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.68 (35461 hom., cov: 34)
  • Exomes 𝑓: 0.63 (294395 hom.)
• Consequence: NOS2 NM_000625.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.751

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).
• BP6: Variant 17-27765605-A-G is Benign according to our data. Variant chr17-27765605-A-G is described in ClinVar as [Benign]. Clinvar id is 2687957.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.751 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.813 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NOS2	NM_000625.4	c.2358T>C	p.Gly786=	synonymous_variant	20/27	ENST00000313735.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NOS2	ENST00000313735.11	c.2358T>C	p.Gly786=	synonymous_variant	20/27	1	NM_000625.4	P2

Frequencies

GnomAD3 genomes AF: 0.677 AC: 103029 AN: 152086 Hom.: 35407 Cov.: 34

Gnomad AFR AF: 0.781

Gnomad AMI AF: 0.763

Gnomad AMR AF: 0.663

Gnomad ASJ AF: 0.686

Gnomad EAS AF: 0.693

Gnomad SAS AF: 0.833

Gnomad FIN AF: 0.610

Gnomad MID AF: 0.801

Gnomad NFE AF: 0.613

Gnomad OTH AF: 0.689

GnomAD3 exomes AF: 0.657 AC: 163615 AN: 248954 Hom.: 54859 AF XY: 0.665 AC XY: 89783 AN XY: 135082

Gnomad AFR exome AF: 0.785

Gnomad AMR exome AF: 0.615

Gnomad ASJ exome AF: 0.681

Gnomad EAS exome AF: 0.690

Gnomad SAS exome AF: 0.832

Gnomad FIN exome AF: 0.600

Gnomad NFE exome AF: 0.608

Gnomad OTH exome AF: 0.654

GnomAD4 exome AF: 0.631 AC: 921436 AN: 1460240 Hom.: 294395 Cov.: 57 AF XY: 0.637 AC XY: 462772 AN XY: 726442

Gnomad4 AFR exome AF: 0.794

Gnomad4 AMR exome AF: 0.619

Gnomad4 ASJ exome AF: 0.685

Gnomad4 EAS exome AF: 0.730

Gnomad4 SAS exome AF: 0.828

Gnomad4 FIN exome AF: 0.596

Gnomad4 NFE exome AF: 0.606

Gnomad4 OTH exome AF: 0.655

GnomAD4 genome AF: 0.678 AC: 103144 AN: 152204 Hom.: 35461 Cov.: 34 AF XY: 0.681 AC XY: 50679 AN XY: 74420

Gnomad4 AFR AF: 0.782

Gnomad4 AMR AF: 0.663

Gnomad4 ASJ AF: 0.686

Gnomad4 EAS AF: 0.692

Gnomad4 SAS AF: 0.834

Gnomad4 FIN AF: 0.610

Gnomad4 NFE AF: 0.613

Gnomad4 OTH AF: 0.691

Alfa AF: 0.643 Hom.: 13721

Bravo AF: 0.679

Asia WGS AF: 0.773 AC: 2691 AN: 3478

EpiCase AF: 0.618

EpiControl AF: 0.621

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	-0.57
Cadd	Benign	8.8
Dann	Benign	0.57

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: rs1060822; hg19: chr17-26092631; COSMIC: COSV58224156;