chr17-27759037-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).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOS2	NM_000625.4	c.3198C>G	p.Ser1066Arg	missense_variant	Exon 26 of 27	ENST00000313735.11	NP_000616.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOS2	ENST00000313735.11	c.3198C>G	p.Ser1066Arg	missense_variant	Exon 26 of 27	1	NM_000625.4	ENSP00000327251.6

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

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 09, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3198C>G (p.S1066R) alteration is located in exon 26 (coding exon 25) of the NOS2 gene. This alteration results from a C to G substitution at nucleotide position 3198, causing the serine (S) at amino acid position 1066 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

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;T;T
M_CAP	Benign	0.038	D
MetaRNN	Benign	0.023	T;T;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;.;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;