Genetic Variant NOS2:c.1476+46C>T (chr17-27774211-G-A) – 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.1476+46C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.218 in 1,366,358 control chromosomes in the GnomAD database, including 33,411 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.20 ( 3124 hom., cov: 32)

Exomes 𝑓: 0.22 ( 30287 hom. )

Consequence

NOS2
NM_000625.4 intron

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.961

Publications

11 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=-0.83).

BP6

Variant 17-27774211-G-A is Benign according to our data. Variant chr17-27774211-G-A is described in ClinVar as Benign. ClinVar VariationId is 2688145.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.278 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOS2	NM_000625.4 link	c.1476+46C>T		intron_variant	Intron 12 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.1476+46C>T		intron_variant	Intron 12 of 26	1	NM_000625.4	ENSP00000327251.6		P35228-1

Frequencies

GnomAD3 genomes

AF:

0.197

AC:

29929

AN:

151696

Hom.:

3125

Cov.:

show subpopulations

Gnomad AFR

AF:

0.127

Gnomad AMI

AF:

0.129

Gnomad AMR

AF:

0.274

Gnomad ASJ

AF:

0.169

Gnomad EAS

AF:

0.291

Gnomad SAS

AF:

0.264

Gnomad FIN

AF:

0.178

Gnomad MID

AF:

0.253

Gnomad NFE

AF:

0.216

Gnomad OTH

AF:

0.213

GnomAD2 exomes

AF:

0.214

AC:

26684

AN:

124684

AF XY:

0.214

show subpopulations

Gnomad AFR exome

AF:

0.122

Gnomad AMR exome

AF:

0.297

Gnomad ASJ exome

AF:

0.173

Gnomad EAS exome

AF:

0.293

Gnomad FIN exome

AF:

0.182

Gnomad NFE exome

AF:

0.207

Gnomad OTH exome

AF:

0.203

GnomAD4 exome

AF:

0.221

AC:

268520

AN:

1214544

Hom.:

30287

Cov.:

AF XY:

0.222

AC XY:

131494

AN XY:

593072

show subpopulations

African (AFR)

AF:

0.123

AC:

3147

AN:

25504

American (AMR)

AF:

0.294

AC:

5841

AN:

19876

Ashkenazi Jewish (ASJ)

AF:

0.177

AC:

3108

AN:

17596

East Asian (EAS)

AF:

0.354

AC:

11170

AN:

31546

South Asian (SAS)

AF:

0.264

AC:

13756

AN:

52018

European-Finnish (FIN)

AF:

0.184

AC:

8645

AN:

47054

Middle Eastern (MID)

AF:

0.269

AC:

1186

AN:

4410

European-Non Finnish (NFE)

AF:

0.218

AC:

210612

AN:

966776

Other (OTH)

AF:

0.222

AC:

11055

AN:

49764

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

9892

19784

29676

39568

49460

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

7816

15632

23448

31264

39080

<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:

0.197

AC:

29938

AN:

151814

Hom.:

3124

Cov.:

AF XY:

0.198

AC XY:

14684

AN XY:

74182

show subpopulations

African (AFR)

AF:

0.127

AC:

5257

AN:

41396

American (AMR)

AF:

0.274

AC:

4179

AN:

15254

Ashkenazi Jewish (ASJ)

AF:

0.169

AC:

586

AN:

3464

East Asian (EAS)

AF:

0.291

AC:

1493

AN:

5138

South Asian (SAS)

AF:

0.264

AC:

1267

AN:

4800

European-Finnish (FIN)

AF:

0.178

AC:

1876

AN:

10530

Middle Eastern (MID)

AF:

0.262

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.216

AC:

14642

AN:

67924

Other (OTH)

AF:

0.211

AC:

444

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

1188

2375

3563

4750

5938

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

326

652

978

1304

1630

<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:

0.173

Hom.:

681

Bravo

AF:

0.198

Asia WGS

AF:

0.255

AC:

890

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 45% of patients studied by a panel of primary immunodeficiencies. Number of patients: 43. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

0.24

(source)

DANN

Benign

0.67

PhyloP100

-0.96

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