17-27773295-A-G

Variant names:

• chr17-27773295-A-G
• rs2248814
• NM_000625.4:c.1477-52T>C

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.1477-52T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.638 in 1,358,722 control chromosomes in the GnomAD database, including 279,574 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.68 (35728 hom., cov: 31)
  • Exomes 𝑓: 0.63 (243846 hom.)
• Consequence: NOS2 NM_000625.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.62
• Publications: 34 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=-0.92).
• BP6: Variant 17-27773295-A-G is Benign according to our data. Variant chr17-27773295-A-G is described in ClinVar as Benign. ClinVar VariationId is 2687962.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.801 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.1477-52T>C		intron	N/A	NP_000616.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOS2	ENST00000313735.11	TSL:1 MANE Select	c.1477-52T>C		intron	N/A	ENSP00000327251.6
	NOS2	ENST00000646938.1		c.1474-52T>C		intron	N/A	ENSP00000494870.1
	NOS2	ENST00000697339.1		c.511-52T>C		intron	N/A	ENSP00000513261.1

Frequencies

GnomAD3 genomes AF: 0.679 AC: 103137 AN: 151914 Hom.: 35672 Cov.: 31

Gnomad AFR AF: 0.809

Gnomad AMI AF: 0.762

Gnomad AMR AF: 0.663

Gnomad ASJ AF: 0.702

Gnomad EAS AF: 0.676

Gnomad SAS AF: 0.800

Gnomad FIN AF: 0.561

Gnomad MID AF: 0.807

Gnomad NFE AF: 0.610

Gnomad OTH AF: 0.688

GnomAD2 exomes AF: 0.651 AC: 156524 AN: 240592 AF XY: 0.656

Gnomad AFR exome AF: 0.814

Gnomad AMR exome AF: 0.618

Gnomad ASJ exome AF: 0.695

Gnomad EAS exome AF: 0.679

Gnomad FIN exome AF: 0.557

Gnomad NFE exome AF: 0.606

Gnomad OTH exome AF: 0.651

GnomAD4 exome AF: 0.632 AC: 762962 AN: 1206692 Hom.: 243846 Cov.: 16 AF XY: 0.638 AC XY: 391115 AN XY: 613298

African (AFR) AF: 0.824 AC: 22954 AN: 27848

American (AMR) AF: 0.621 AC: 25290 AN: 40750

Ashkenazi Jewish (ASJ) AF: 0.700 AC: 16988 AN: 24268

East Asian (EAS) AF: 0.727 AC: 27832 AN: 38300

South Asian (SAS) AF: 0.796 AC: 63956 AN: 80324

European-Finnish (FIN) AF: 0.558 AC: 29167 AN: 52234

Middle Eastern (MID) AF: 0.782 AC: 4006 AN: 5124

European-Non Finnish (NFE) AF: 0.608 AC: 538999 AN: 886100

Other (OTH) AF: 0.653 AC: 33770 AN: 51744

GnomAD4 genome AF: 0.679 AC: 103253 AN: 152030 Hom.: 35728 Cov.: 31 AF XY: 0.680 AC XY: 50501 AN XY: 74300

African (AFR) AF: 0.809 AC: 33538 AN: 41474

American (AMR) AF: 0.664 AC: 10141 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.702 AC: 2436 AN: 3468

East Asian (EAS) AF: 0.676 AC: 3478 AN: 5142

South Asian (SAS) AF: 0.801 AC: 3857 AN: 4814

European-Finnish (FIN) AF: 0.561 AC: 5931 AN: 10574

Middle Eastern (MID) AF: 0.816 AC: 240 AN: 294

European-Non Finnish (NFE) AF: 0.610 AC: 41488 AN: 67968

Other (OTH) AF: 0.690 AC: 1452 AN: 2104

Alfa AF: 0.592 Hom.: 3500

Bravo AF: 0.686

Asia WGS AF: 0.762 AC: 2651 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

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 85% of patients studied by a panel of primary immunodeficiencies. Number of patients: 81. Only high quality variants are reported.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.18
DANN	Benign	0.28
PhyloP100		-2.6
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: rs2248814; hg19: chr17-26100321; COSMIC: COSV107379314;