17-27762841-T-C

Variant names:

• chr17-27762841-T-C
• rs1060826
• NM_000625.4:c.2757A>G

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.2757A>G​(p.Thr919Thr) 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 1,560,140 control chromosomes in the GnomAD database, including 318,832 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.68 (35176 hom., cov: 31)
  • Exomes 𝑓: 0.63 (283656 hom.)
• Consequence: NOS2 NM_000625.4 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: -1.61
• Publications: 42 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=-0.84).
• BP6: Variant 17-27762841-T-C is Benign according to our data. Variant chr17-27762841-T-C is described in ClinVar as Benign. ClinVar VariationId is 2687955.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-1.61 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.813 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000625.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOS2	NM_000625.4	MANE Select	c.2757A>G	p.Thr919Thr	synonymous	Exon 22 of 27	NP_000616.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOS2	ENST00000313735.11	TSL:1 MANE Select	c.2757A>G	p.Thr919Thr	synonymous	Exon 22 of 27	ENSP00000327251.6
	NOS2	ENST00000646938.1		c.2754A>G	p.Thr918Thr	synonymous	Exon 21 of 26	ENSP00000494870.1
	NOS2	ENST00000697339.1		c.1719A>G	p.Thr573Thr	synonymous	Exon 14 of 19	ENSP00000513261.1

Frequencies

GnomAD3 genomes AF: 0.676 AC: 102590 AN: 151828 Hom.: 35121 Cov.: 31

Gnomad AFR AF: 0.773

Gnomad AMI AF: 0.765

Gnomad AMR AF: 0.662

Gnomad ASJ AF: 0.689

Gnomad EAS AF: 0.690

Gnomad SAS AF: 0.833

Gnomad FIN AF: 0.613

Gnomad MID AF: 0.801

Gnomad NFE AF: 0.614

Gnomad OTH AF: 0.688

GnomAD2 exomes AF: 0.660 AC: 113051 AN: 171212 AF XY: 0.668

Gnomad AFR exome AF: 0.778

Gnomad AMR exome AF: 0.614

Gnomad ASJ exome AF: 0.683

Gnomad EAS exome AF: 0.686

Gnomad FIN exome AF: 0.599

Gnomad NFE exome AF: 0.610

Gnomad OTH exome AF: 0.660

GnomAD4 exome AF: 0.631 AC: 888475 AN: 1408194 Hom.: 283656 Cov.: 47 AF XY: 0.637 AC XY: 442799 AN XY: 695626

African (AFR) AF: 0.785 AC: 25321 AN: 32250

American (AMR) AF: 0.620 AC: 22368 AN: 36104

Ashkenazi Jewish (ASJ) AF: 0.686 AC: 17241 AN: 25116

East Asian (EAS) AF: 0.731 AC: 27100 AN: 37062

South Asian (SAS) AF: 0.827 AC: 65975 AN: 79756

European-Finnish (FIN) AF: 0.597 AC: 29739 AN: 49804

Middle Eastern (MID) AF: 0.773 AC: 3752 AN: 4852

European-Non Finnish (NFE) AF: 0.607 AC: 658621 AN: 1084866

Other (OTH) AF: 0.657 AC: 38358 AN: 58384

GnomAD4 genome AF: 0.676 AC: 102706 AN: 151946 Hom.: 35176 Cov.: 31 AF XY: 0.679 AC XY: 50432 AN XY: 74230

African (AFR) AF: 0.773 AC: 32053 AN: 41444

American (AMR) AF: 0.663 AC: 10128 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.689 AC: 2389 AN: 3468

East Asian (EAS) AF: 0.689 AC: 3544 AN: 5140

South Asian (SAS) AF: 0.835 AC: 4003 AN: 4796

European-Finnish (FIN) AF: 0.613 AC: 6470 AN: 10556

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

European-Non Finnish (NFE) AF: 0.614 AC: 41738 AN: 67960

Other (OTH) AF: 0.690 AC: 1448 AN: 2100

Alfa AF: 0.638 Hom.: 9680

Bravo AF: 0.677

Asia WGS AF: 0.773 AC: 2689 AN: 3478

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.053
DANN	Benign	0.46
PhyloP100		-1.6
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1060826; hg19: chr17-26089867; COSMIC: COSV58226384;