rs5272

Positions:

• chr1-186674705-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_000963.4(PTGS2):​c.1463A>G​(p.Glu488Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency: Genomes: not found (cov: 33)
• Consequence: PTGS2 NM_000963.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.82

Genes affected

PTGS2 (HGNC:9605): (prostaglandin-endoperoxide synthase 2) Prostaglandin-endoperoxide synthase (PTGS), also known as cyclooxygenase, is the key enzyme in prostaglandin biosynthesis, and acts both as a dioxygenase and as a peroxidase. There are two isozymes of PTGS: a constitutive PTGS1 and an inducible PTGS2, which differ in their regulation of expression and tissue distribution. This gene encodes the inducible isozyme. It is regulated by specific stimulatory events, suggesting that it is responsible for the prostanoid biosynthesis involved in inflammation and mitogenesis. [provided by RefSeq, Feb 2009]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.884

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTGS2	NM_000963.4	c.1463A>G	p.Glu488Gly	missense_variant	10/10	ENST00000367468.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTGS2	ENST00000367468.10	c.1463A>G	p.Glu488Gly	missense_variant	10/10	1	NM_000963.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.36
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.74	D
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.88	D
MetaSVM	Uncertain	0.69	D
MutationAssessor	Pathogenic	3.7	H
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-6.6	D
REVEL	Pathogenic	0.83
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.94
MutPred		0.51		Loss of sheet (P = 0.302);
MVP		0.92
MPC		1.8
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.87
gMVP		0.97

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

Publications

LitVar

Other links and lift over

dbSNP: rs5272; hg19: chr1-186643837;