rs2297512

Variant names:

• chr17-27765529-G-A
• rs2297512
• NM_000625.4:c.2428+6C>T

Your query was ambiguous. Multiple possible variants found:

• chr17-27765529-G-A
• chr17-27765529-G-T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000625.4(NOS2):​c.2428+6C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.633 in 1,588,414 control chromosomes in the GnomAD database, including 322,144 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.68 (35219 hom., cov: 33)
  • Exomes 𝑓: 0.63 (286925 hom.)
• Consequence: NOS2 NM_000625.4 splice_region, intron
• Scores: Splicing: ADA: 0.0001130
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 0.158
• Publications: 13 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 17-27765529-G-A is Benign according to our data. Variant chr17-27765529-G-A is described in ClinVar as Benign. ClinVar VariationId is 2687956.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.812 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOS2	NM_000625.4	c.2428+6C>T		splice_region_variant, intron_variant	Intron 20 of 26	ENST00000313735.11	NP_000616.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOS2	ENST00000313735.11	c.2428+6C>T		splice_region_variant, intron_variant	Intron 20 of 26	1	NM_000625.4	ENSP00000327251.6

Frequencies

GnomAD3 genomes AF: 0.675 AC: 102615 AN: 152026 Hom.: 35165 Cov.: 33

Gnomad AFR AF: 0.780

Gnomad AMI AF: 0.763

Gnomad AMR AF: 0.662

Gnomad ASJ AF: 0.686

Gnomad EAS AF: 0.692

Gnomad SAS AF: 0.833

Gnomad FIN AF: 0.591

Gnomad MID AF: 0.801

Gnomad NFE AF: 0.612

Gnomad OTH AF: 0.689

GnomAD2 exomes AF: 0.648 AC: 148417 AN: 228906 AF XY: 0.655

Gnomad AFR exome AF: 0.783

Gnomad AMR exome AF: 0.609

Gnomad ASJ exome AF: 0.666

Gnomad EAS exome AF: 0.687

Gnomad FIN exome AF: 0.578

Gnomad NFE exome AF: 0.601

Gnomad OTH exome AF: 0.647

GnomAD4 exome AF: 0.628 AC: 902060 AN: 1436270 Hom.: 286925 Cov.: 38 AF XY: 0.634 AC XY: 451402 AN XY: 712348

African (AFR) AF: 0.792 AC: 26080 AN: 32928

American (AMR) AF: 0.614 AC: 25980 AN: 42318

Ashkenazi Jewish (ASJ) AF: 0.680 AC: 16753 AN: 24622

East Asian (EAS) AF: 0.730 AC: 28576 AN: 39158

South Asian (SAS) AF: 0.826 AC: 67986 AN: 82310

European-Finnish (FIN) AF: 0.582 AC: 30077 AN: 51688

Middle Eastern (MID) AF: 0.771 AC: 3245 AN: 4210

European-Non Finnish (NFE) AF: 0.604 AC: 664789 AN: 1099896

Other (OTH) AF: 0.652 AC: 38574 AN: 59140

GnomAD4 genome AF: 0.675 AC: 102730 AN: 152144 Hom.: 35219 Cov.: 33 AF XY: 0.678 AC XY: 50404 AN XY: 74366

African (AFR) AF: 0.780 AC: 32387 AN: 41530

American (AMR) AF: 0.663 AC: 10145 AN: 15304

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

East Asian (EAS) AF: 0.692 AC: 3578 AN: 5174

South Asian (SAS) AF: 0.834 AC: 4012 AN: 4812

European-Finnish (FIN) AF: 0.591 AC: 6254 AN: 10578

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

European-Non Finnish (NFE) AF: 0.612 AC: 41585 AN: 67962

Other (OTH) AF: 0.690 AC: 1454 AN: 2106

Alfa AF: 0.652 Hom.: 9660

Bravo AF: 0.679

Asia WGS AF: 0.773 AC: 2691 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 v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	8.7
DANN	Benign	0.48
PhyloP100		0.16
Mutation Taster		=94/6	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00011
dbscSNV1_RF	Benign	0.0020
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: rs2297512; hg19: chr17-26092555;