17-27759037-G-C

Variant names:

• chr17-27759037-G-C
• rs139005303
• NM_000625.4:c.3198C>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_000625.4(NOS2):​c.3198C>G​(p.Ser1066Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000056 in 1,607,074 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00034 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000026 (0 hom.)
• Consequence: NOS2 NM_000625.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.37
• Publications: 1 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.023434281).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOS2	NM_000625.4	MANE Select	c.3198C>G	p.Ser1066Arg	missense	Exon 26 of 27	NP_000616.3	P35228-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOS2	ENST00000313735.11	TSL:1 MANE Select	c.3198C>G	p.Ser1066Arg	missense	Exon 26 of 27	ENSP00000327251.6	P35228-1
	NOS2	ENST00000886820.1		c.3198C>G	p.Ser1066Arg	missense	Exon 26 of 27	ENSP00000556879.1
	NOS2	ENST00000646938.1		c.3195C>G	p.Ser1065Arg	missense	Exon 25 of 26	ENSP00000494870.1	A0A2R8YDS4

Frequencies

GnomAD3 genomes AF: 0.000342 AC: 52 AN: 152254 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000989

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000523

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.0000624 AC: 15 AN: 240446 AF XY: 0.0000382

Gnomad AFR exome AF: 0.000788

Gnomad AMR exome AF: 0.0000909

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000261 AC: 38 AN: 1454820 Hom.: 0 Cov.: 31 AF XY: 0.0000249 AC XY: 18 AN XY: 723686

African (AFR) AF: 0.000845 AC: 28 AN: 33142

American (AMR) AF: 0.000137 AC: 6 AN: 43880

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25848

East Asian (EAS) AF: 0.00 AC: 0 AN: 39218

South Asian (SAS) AF: 0.00 AC: 0 AN: 85466

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52346

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5476

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1109384

Other (OTH) AF: 0.0000666 AC: 4 AN: 60060

GnomAD4 genome AF: 0.000342 AC: 52 AN: 152254 Hom.: 0 Cov.: 33 AF XY: 0.000390 AC XY: 29 AN XY: 74382

African (AFR) AF: 0.000989 AC: 41 AN: 41470

American (AMR) AF: 0.000523 AC: 8 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68042

Other (OTH) AF: 0.00143 AC: 3 AN: 2094

Alfa AF: 0.0000678 Hom.: 0

Bravo AF: 0.000389

ESP6500AA AF: 0.000682 AC: 3

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000824 AC: 10

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	0.56
DANN	Benign	0.96
DEOGEN2	Benign	0.25	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.042	N
LIST_S2	Benign	0.19	T
M_CAP	Benign	0.038	D
MetaRNN	Benign	0.023	T
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	0.78	N
PhyloP100		-1.4
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.22
Sift	Benign	0.24	T
Sift4G	Benign	0.41	T
Polyphen		0.015	B
Vest4		0.24
MutPred		0.41		Gain of MoRF binding (P = 0.0115)
MVP		0.36
MPC		0.18
ClinPred		0.010	T
GERP RS		-5.3
Varity_R		0.16
gMVP		0.40
Mutation Taster		=94/6	polymorphism

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: rs139005303; hg19: chr17-26086063; COSMIC: COSV100569521; COSMIC: COSV100569521;