rs2297518

Positions:

• chr17-27769571-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000625.4(NOS2):​c.1823C>T​(p.Ser608Leu) variant causes a missense change. The variant allele was found at a frequency of 0.184 in 1,608,552 control chromosomes in the GnomAD database, including 28,406 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.17 (2373 hom., cov: 33)
  • Exomes 𝑓: 0.18 (26033 hom.)
• Consequence: NOS2 NM_000625.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 6.41

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0028576553).
• BP6: Variant 17-27769571-G-A is Benign according to our data. Variant chr17-27769571-G-A is described in ClinVar as [Benign]. Clinvar id is 2688228.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.191 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NOS2	NM_000625.4	c.1823C>T	p.Ser608Leu	missense_variant	16/27	ENST00000313735.11	NP_000616.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NOS2	ENST00000313735.11	c.1823C>T	p.Ser608Leu	missense_variant	16/27	1	NM_000625.4	ENSP00000327251	P2

Frequencies

GnomAD3 genomes AF: 0.172 AC: 26142 AN: 151996 Hom.: 2375 Cov.: 33

Gnomad AFR AF: 0.121

Gnomad AMI AF: 0.458

Gnomad AMR AF: 0.168

Gnomad ASJ AF: 0.256

Gnomad EAS AF: 0.150

Gnomad SAS AF: 0.173

Gnomad FIN AF: 0.188

Gnomad MID AF: 0.241

Gnomad NFE AF: 0.194

Gnomad OTH AF: 0.197

GnomAD3 exomes AF: 0.177 AC: 44586 AN: 251380 Hom.: 4216 AF XY: 0.183 AC XY: 24836 AN XY: 135860

Gnomad AFR exome AF: 0.118

Gnomad AMR exome AF: 0.129

Gnomad ASJ exome AF: 0.257

Gnomad EAS exome AF: 0.148

Gnomad SAS exome AF: 0.181

Gnomad FIN exome AF: 0.181

Gnomad NFE exome AF: 0.195

Gnomad OTH exome AF: 0.198

GnomAD4 exome AF: 0.185 AC: 269171 AN: 1456438 Hom.: 26033 Cov.: 31 AF XY: 0.186 AC XY: 134655 AN XY: 724896

Gnomad4 AFR exome AF: 0.118

Gnomad4 AMR exome AF: 0.133

Gnomad4 ASJ exome AF: 0.253

Gnomad4 EAS exome AF: 0.102

Gnomad4 SAS exome AF: 0.180

Gnomad4 FIN exome AF: 0.179

Gnomad4 NFE exome AF: 0.191

Gnomad4 OTH exome AF: 0.187

GnomAD4 genome AF: 0.172 AC: 26144 AN: 152114 Hom.: 2373 Cov.: 33 AF XY: 0.173 AC XY: 12838 AN XY: 74374

Gnomad4 AFR AF: 0.121

Gnomad4 AMR AF: 0.168

Gnomad4 ASJ AF: 0.256

Gnomad4 EAS AF: 0.149

Gnomad4 SAS AF: 0.173

Gnomad4 FIN AF: 0.188

Gnomad4 NFE AF: 0.194

Gnomad4 OTH AF: 0.195

Alfa AF: 0.192 Hom.: 7270

Bravo AF: 0.170

TwinsUK AF: 0.200 AC: 743

ALSPAC AF: 0.189 AC: 727

ESP6500AA AF: 0.113 AC: 500

ESP6500EA AF: 0.195 AC: 1680

ExAC AF: 0.178 AC: 21575

Asia WGS AF: 0.140 AC: 486 AN: 3478

EpiCase AF: 0.203

EpiControl AF: 0.197

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

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 32% of patients studied by a panel of primary immunodeficiencies. Number of patients: 30. Only high quality variants are reported. -

NOS2-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 04, 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
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.34
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.38	T;.;.
Eigen	Benign	0.19
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.92	D;D;D
MetaRNN	Benign	0.0029	T;T;T
MetaSVM	Benign	-1.2	T
MutationAssessor	Benign	1.5	L;.;.
MutationTaster	Benign	0.00095	P
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-2.8	D;.;.
REVEL	Benign	0.25
Sift	Benign	0.12	T;.;.
Sift4G	Benign	0.10	T;.;T
Polyphen		0.92	P;.;.
Vest4		0.24
MPC		2.6
ClinPred		0.023	T
GERP RS		5.3
Varity_R		0.46
gMVP		0.54

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: rs2297518; hg19: chr17-26096597; COSMIC: COSV58225005;