17-27765605-A-G

Variant names:

• chr17-27765605-A-G
• rs1060822
• NM_000625.4:c.2358T>C

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BA1

The NM_000625.4(NOS2):​c.2358T>C​(p.Gly786Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.635 in 1,612,444 control chromosomes in the GnomAD database, including 329,856 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.68 (35461 hom., cov: 34)
  • Exomes 𝑓: 0.63 (294395 hom.)
• Consequence: NOS2 NM_000625.4 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 0.751
• Publications: 19 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 -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).
• BP6: Variant 17-27765605-A-G is Benign according to our data. Variant chr17-27765605-A-G is described in ClinVar as Benign. ClinVar VariationId is 2687957.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.751 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.813 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOS2	NM_000625.4	c.2358T>C	p.Gly786Gly	synonymous_variant	Exon 20 of 27	ENST00000313735.11	NP_000616.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOS2	ENST00000313735.11	c.2358T>C	p.Gly786Gly	synonymous_variant	Exon 20 of 27	1	NM_000625.4	ENSP00000327251.6

Frequencies

GnomAD3 genomes AF: 0.677 AC: 103029 AN: 152086 Hom.: 35407 Cov.: 34

Gnomad AFR AF: 0.781

Gnomad AMI AF: 0.763

Gnomad AMR AF: 0.663

Gnomad ASJ AF: 0.686

Gnomad EAS AF: 0.693

Gnomad SAS AF: 0.833

Gnomad FIN AF: 0.610

Gnomad MID AF: 0.801

Gnomad NFE AF: 0.613

Gnomad OTH AF: 0.689

GnomAD2 exomes AF: 0.657 AC: 163615 AN: 248954 AF XY: 0.665

Gnomad AFR exome AF: 0.785

Gnomad AMR exome AF: 0.615

Gnomad ASJ exome AF: 0.681

Gnomad EAS exome AF: 0.690

Gnomad FIN exome AF: 0.600

Gnomad NFE exome AF: 0.608

Gnomad OTH exome AF: 0.654

GnomAD4 exome AF: 0.631 AC: 921436 AN: 1460240 Hom.: 294395 Cov.: 57 AF XY: 0.637 AC XY: 462772 AN XY: 726442

African (AFR) AF: 0.794 AC: 26562 AN: 33448

American (AMR) AF: 0.619 AC: 27661 AN: 44660

Ashkenazi Jewish (ASJ) AF: 0.685 AC: 17889 AN: 26120

East Asian (EAS) AF: 0.730 AC: 28985 AN: 39688

South Asian (SAS) AF: 0.828 AC: 71390 AN: 86194

European-Finnish (FIN) AF: 0.596 AC: 31464 AN: 52758

Middle Eastern (MID) AF: 0.772 AC: 4121 AN: 5336

European-Non Finnish (NFE) AF: 0.606 AC: 673867 AN: 1111728

Other (OTH) AF: 0.655 AC: 39497 AN: 60308

GnomAD4 genome AF: 0.678 AC: 103144 AN: 152204 Hom.: 35461 Cov.: 34 AF XY: 0.681 AC XY: 50679 AN XY: 74420

African (AFR) AF: 0.782 AC: 32473 AN: 41552

American (AMR) AF: 0.663 AC: 10141 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.686 AC: 2381 AN: 3472

East Asian (EAS) AF: 0.692 AC: 3575 AN: 5164

South Asian (SAS) AF: 0.834 AC: 4028 AN: 4828

European-Finnish (FIN) AF: 0.610 AC: 6459 AN: 10590

Middle Eastern (MID) AF: 0.810 AC: 238 AN: 294

European-Non Finnish (NFE) AF: 0.613 AC: 41693 AN: 67994

Other (OTH) AF: 0.691 AC: 1460 AN: 2112

Alfa AF: 0.644 Hom.: 13952

Bravo AF: 0.679

Asia WGS AF: 0.773 AC: 2691 AN: 3478

EpiCase AF: 0.618

EpiControl AF: 0.621

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 87% of patients studied by a panel of primary immunodeficiencies. Number of patients: 83. Only high quality variants are reported.

NOS2-related disorder Benign:1

Oct 17, 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 v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	8.8
DANN	Benign	0.57
PhyloP100		0.75
Mutation Taster		=100/0	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: rs1060822; hg19: chr17-26092631; COSMIC: COSV58224156;