rs3218622

chr1-186676873-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_000963.4(PTGS2):c.683G>A(p.Arg228His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000463 in 1,609,950 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign 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: 𝑓 0.00025 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00048 (5 hom.)
• Consequence: PTGS2 NM_000963.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.27

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 Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006051779).
• BS2: High AC in GnomAd at 38 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTGS2	NM_000963.4	c.683G>A	p.Arg228His	missense_variant	6/10	ENST00000367468.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTGS2	ENST00000367468.10	c.683G>A	p.Arg228His	missense_variant	6/10	1	NM_000963.4	P1

Frequencies

GnomAD3 genomes AF: 0.000250 AC: 38 AN: 152082 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00443

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000695 AC: 174 AN: 250538 Hom.: 0 AF XY: 0.000613 AC XY: 83 AN XY: 135464

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00134

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00445

Gnomad SAS exome AF: 0.00115

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000793

Gnomad OTH exome AF: 0.000490

GnomAD4 exome AF: 0.000485 AC: 707 AN: 1457750 Hom.: 5 Cov.: 31 AF XY: 0.000483 AC XY: 350 AN XY: 724970

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00112

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0106

Gnomad4 SAS exome AF: 0.00116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000104

Gnomad4 OTH exome AF: 0.000332

GnomAD4 genome AF: 0.000250 AC: 38 AN: 152200 Hom.: 0 Cov.: 33 AF XY: 0.000296 AC XY: 22 AN XY: 74406

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00444

Gnomad4 SAS AF: 0.00208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000250 Hom.: 0

Bravo AF: 0.000306

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000774 AC: 94

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.050
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.46
Cadd	Benign	20
Dann	Benign	0.18
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.50
FATHMM_MKL	Benign	0.28	N
LIST_S2	Benign	0.63	T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.0061	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-2.2	N
MutationTaster	Benign	1.0	N
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	4.5	N
REVEL	Benign	0.13
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.052
MVP		0.31
MPC		0.81
ClinPred		0.026	T
GERP RS		5.5
Varity_R		0.12
gMVP		0.15

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: rs3218622; hg19: chr1-186646005; COSMIC: COSV66569657; COSMIC: COSV66569657;