Variant 17-27759037-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_000625.4(NOS2):c.3198C>G(p.Ser1066Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000056 in 1,607,074 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00034 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000026 ( 0 hom. )

Consequence

NOS2
NM_000625.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.37

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]

NOS2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.023434281).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NOS2	NM_000625.4 linkuse as main transcript	c.3198C>G	p.Ser1066Arg	missense_variant	26/27	ENST00000313735.11	NP_000616.3	P35228-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NOS2	ENST00000313735.11 linkuse as main transcript	c.3198C>G	p.Ser1066Arg	missense_variant	26/27	1	NM_000625.4	ENSP00000327251.6		P35228-1

Frequencies

GnomAD3 genomes

AF:

0.000342

AC:

AN:

152254

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000989

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000523

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.0000624

AC:

AN:

240446

Hom.:

AF XY:

0.0000382

AC XY:

AN XY:

130922

show subpopulations

Gnomad AFR exome

AF:

0.000788

Gnomad AMR exome

AF:

0.0000909

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000261

AC:

AN:

1454820

Hom.:

Cov.:

AF XY:

0.0000249

AC XY:

AN XY:

723686

show subpopulations

Gnomad4 AFR exome

AF:

0.000845

Gnomad4 AMR exome

AF:

0.000137

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000666

GnomAD4 genome

AF:

0.000342

AC:

AN:

152254

Hom.:

Cov.:

AF XY:

0.000390

AC XY:

AN XY:

74382

show subpopulations

Gnomad4 AFR

AF:

0.000989

Gnomad4 AMR

AF:

0.000523

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00143

Alfa

AF:

0.0000678

Hom.:

Bravo

AF:

0.000389

ESP6500AA

AF:

0.000682

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 09, 2021

The c.3198C>G (p.S1066R) alteration is located in exon 26 (coding exon 25) of the NOS2 gene. This alteration results from a C to G substitution at nucleotide position 3198, causing the serine (S) at amino acid position 1066 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.32

CADD

Benign

0.56

DANN

Benign

0.96

DEOGEN2

Benign

0.25

T;.;.

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.042

LIST_S2

Benign

0.19

T;T;T

M_CAP

Benign

0.038

MetaRNN

Benign

0.023

T;T;T

MetaSVM

Benign

-0.76

MutationAssessor

Benign

0.78

N;.;.

PrimateAI

Benign

0.29

PROVEAN

Benign

-1.2

N;.;.

REVEL

Benign

0.22

Sift

Benign

0.24

T;.;.

Sift4G

Benign

0.41

T;.;T

Polyphen

0.015

B;.;.

Vest4

0.24

MutPred

0.41

Gain of MoRF binding (P = 0.0115);.;.;

MVP

0.36

MPC

0.18

ClinPred

0.010

GERP RS

-5.3

Varity_R

0.16

gMVP

0.40

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over