Genetic Variant NOS2:c.864+22A>G (chr17-27781014-T-C) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBA1

The NM_000625.4(NOS2):c.864+22A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.614 in 1,608,076 control chromosomes in the GnomAD database, including 306,360 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.67 ( 34653 hom., cov: 34)

Exomes 𝑓: 0.61 ( 271707 hom. )

Consequence

NOS2
NM_000625.4 intron

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.531

Publications

13 publications found

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 Gene-Disease associations (from GenCC):

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

NOS2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.86).

BP6

Variant 17-27781014-T-C is Benign according to our data. Variant chr17-27781014-T-C is described in ClinVar as Benign. ClinVar VariationId is 2687960.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.796 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOS2	NM_000625.4 link	c.864+22A>G		intron_variant	Intron 8 of 26	ENST00000313735.11	NP_000616.3	P35228-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOS2	ENST00000313735.11 link	c.864+22A>G		intron_variant	Intron 8 of 26	1	NM_000625.4	ENSP00000327251.6		P35228-1

Frequencies

GnomAD3 genomes

AF:

0.668

AC:

101629

AN:

152060

Hom.:

34595

Cov.:

show subpopulations

Gnomad AFR

AF:

0.803

Gnomad AMI

AF:

0.747

Gnomad AMR

AF:

0.689

Gnomad ASJ

AF:

0.651

Gnomad EAS

AF:

0.527

Gnomad SAS

AF:

0.739

Gnomad FIN

AF:

0.603

Gnomad MID

AF:

0.734

Gnomad NFE

AF:

0.597

Gnomad OTH

AF:

0.656

GnomAD2 exomes

AF:

0.641

AC:

158540

AN:

247328

AF XY:

0.641

show subpopulations

Gnomad AFR exome

AF:

0.807

Gnomad AMR exome

AF:

0.713

Gnomad ASJ exome

AF:

0.648

Gnomad EAS exome

AF:

0.541

Gnomad FIN exome

AF:

0.600

Gnomad NFE exome

AF:

0.594

Gnomad OTH exome

AF:

0.637

GnomAD4 exome

AF:

0.608

AC:

884905

AN:

1455898

Hom.:

271707

Cov.:

AF XY:

0.611

AC XY:

441875

AN XY:

723412

show subpopulations

African (AFR)

AF:

0.817

AC:

27312

AN:

33416

American (AMR)

AF:

0.710

AC:

31594

AN:

44524

Ashkenazi Jewish (ASJ)

AF:

0.651

AC:

16805

AN:

25818

East Asian (EAS)

AF:

0.523

AC:

20694

AN:

39592

South Asian (SAS)

AF:

0.730

AC:

62577

AN:

85738

European-Finnish (FIN)

AF:

0.599

AC:

31517

AN:

52592

Middle Eastern (MID)

AF:

0.730

AC:

4200

AN:

5750

European-Non Finnish (NFE)

AF:

0.589

AC:

652751

AN:

1108362

Other (OTH)

AF:

0.623

AC:

37455

AN:

60106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

19626

39252

58877

78503

98129

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

18092

36184

54276

72368

90460

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.669

AC:

101747

AN:

152178

Hom.:

34653

Cov.:

AF XY:

0.671

AC XY:

49945

AN XY:

74380

show subpopulations

African (AFR)

AF:

0.803

AC:

33382

AN:

41556

American (AMR)

AF:

0.689

AC:

10541

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.651

AC:

2257

AN:

3468

East Asian (EAS)

AF:

0.526

AC:

2707

AN:

5144

South Asian (SAS)

AF:

0.740

AC:

3562

AN:

4816

European-Finnish (FIN)

AF:

0.603

AC:

6381

AN:

10586

Middle Eastern (MID)

AF:

0.738

AC:

217

AN:

294

European-Non Finnish (NFE)

AF:

0.598

AC:

40629

AN:

67996

Other (OTH)

AF:

0.658

AC:

1390

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

1792

3584

5375

7167

8959

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

800

1600

2400

3200

4000

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.637

Hom.:

5922

Bravo

AF:

0.679

Asia WGS

AF:

0.628

AC:

2188

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

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 86% of patients studied by a panel of primary immunodeficiencies. Number of patients: 82. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

0.95

(source)

DANN

Benign

0.15

PhyloP100

-0.53

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over