NM_000625.4:c.1823C>T

Variant names:

• chr17-27769571-G-A
• rs2297518
• NM_000625.4:c.1823C>T

Variant summary

Our verdict is Benign. The variant received -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 (★).

• 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
• Publications: 244 publications found

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]

NOS2 Gene-Disease associations (from GenCC):

• schizophrenia

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000625.4. 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
	NOS2	NM_000625.4	MANE Select	c.1823C>T	p.Ser608Leu	missense	Exon 16 of 27	NP_000616.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOS2	ENST00000313735.11	TSL:1 MANE Select	c.1823C>T	p.Ser608Leu	missense	Exon 16 of 27	ENSP00000327251.6
	NOS2	ENST00000646938.1		c.1820C>T	p.Ser607Leu	missense	Exon 15 of 26	ENSP00000494870.1
	NOS2	ENST00000697339.1		c.857C>T	p.Ser286Leu	missense	Exon 8 of 19	ENSP00000513261.1

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

GnomAD2 exomes AF: 0.177 AC: 44586 AN: 251380 AF XY: 0.183

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 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

African (AFR) AF: 0.118 AC: 3955 AN: 33392

American (AMR) AF: 0.133 AC: 5966 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.253 AC: 6589 AN: 26082

East Asian (EAS) AF: 0.102 AC: 4056 AN: 39686

South Asian (SAS) AF: 0.180 AC: 15467 AN: 86112

European-Finnish (FIN) AF: 0.179 AC: 9559 AN: 53404

Middle Eastern (MID) AF: 0.229 AC: 1316 AN: 5748

European-Non Finnish (NFE) AF: 0.191 AC: 211002 AN: 1107092

Other (OTH) AF: 0.187 AC: 11261 AN: 60212

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

African (AFR) AF: 0.121 AC: 5033 AN: 41494

American (AMR) AF: 0.168 AC: 2565 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.256 AC: 890 AN: 3470

East Asian (EAS) AF: 0.149 AC: 774 AN: 5182

South Asian (SAS) AF: 0.173 AC: 834 AN: 4814

European-Finnish (FIN) AF: 0.188 AC: 1991 AN: 10578

Middle Eastern (MID) AF: 0.241 AC: 71 AN: 294

European-Non Finnish (NFE) AF: 0.194 AC: 13156 AN: 67970

Other (OTH) AF: 0.195 AC: 412 AN: 2114

Alfa AF: 0.188 Hom.: 13156

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

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 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

Nov 04, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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 v4.9

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
MetaRNN	Benign	0.0029	T
MetaSVM	Benign	-1.2	T
MutationAssessor	Benign	1.5	L
PhyloP100		6.4
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-2.8	D
REVEL	Benign	0.25
Sift	Benign	0.12	T
Sift4G	Benign	0.10	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
Mutation Taster		=88/12	polymorphism (auto)

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

Other links and lift over

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