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rs2297518

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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

Scores

1
5
12

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 6.41
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 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_multiple_submitters_no_conflicts, 2 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 UniProt
NOS2NM_000625.4 linkuse as main transcriptc.1823C>T p.Ser608Leu missense_variant 16/27 ENST00000313735.11

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
NOS2ENST00000313735.11 linkuse as main transcriptc.1823C>T p.Ser608Leu missense_variant 16/271 NM_000625.4 P2P35228-1

Frequencies

GnomAD3 genomes
AF:
0.172
AC:
26142
AN:
151996
Hom.:
2375
Cov.:
33
show subpopulations
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
show subpopulations
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
show subpopulations
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
show subpopulations
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, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:1
Benign, criteria provided, single submitterclinical testingUnidad de Genómica Garrahan, Hospital de Pediatría GarrahanJan 24, 2024This 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 condition Benign:1
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesNov 04, 2019This 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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

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