1-186674409-C-T

Variant names:

• chr1-186674409-C-T
• rs3218625
• NM_000963.4:c.1759G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_000963.4(PTGS2):​c.1759G>A​(p.Gly587Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000491 in 1,613,804 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00064 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00048 (4 hom.)
• Consequence: PTGS2 NM_000963.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.327
• Publications: 29 publications found

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

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0026129186).
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000644 (98/152126) while in subpopulation EAS AF = 0.018 (93/5180). AF 95% confidence interval is 0.015. There are 1 homozygotes in GnomAd4. There are 54 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 98 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000963.4. 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
	PTGS2	NM_000963.4	MANE Select	c.1759G>A	p.Gly587Arg	missense	Exon 10 of 10	NP_000954.1	P35354

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTGS2	ENST00000367468.10	TSL:1 MANE Select	c.1759G>A	p.Gly587Arg	missense	Exon 10 of 10	ENSP00000356438.5	P35354
	PTGS2	ENST00000490885.6	TSL:1	n.2174G>A		non_coding_transcript_exon	Exon 9 of 9
	PTGS2	ENST00000559627.1	TSL:1	n.*1157G>A		non_coding_transcript_exon	Exon 10 of 10	ENSP00000454130.1	Q6ZYK7

Frequencies

GnomAD3 genomes AF: 0.000645 AC: 98 AN: 152008 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0179

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00163 AC: 409 AN: 251448 AF XY: 0.00146

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0219

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000475 AC: 695 AN: 1461678 Hom.: 4 Cov.: 30 AF XY: 0.000441 AC XY: 321 AN XY: 727150

African (AFR) AF: 0.00 AC: 0 AN: 33468

American (AMR) AF: 0.000112 AC: 5 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.0163 AC: 648 AN: 39698

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000126 AC: 14 AN: 1111830

Other (OTH) AF: 0.000431 AC: 26 AN: 60390

GnomAD4 genome AF: 0.000644 AC: 98 AN: 152126 Hom.: 1 Cov.: 33 AF XY: 0.000726 AC XY: 54 AN XY: 74342

African (AFR) AF: 0.0000241 AC: 1 AN: 41498

American (AMR) AF: 0.000131 AC: 2 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.0180 AC: 93 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10544

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68014

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.000578 Hom.: 1

Bravo AF: 0.000884

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.00168 AC: 204

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	6.4
DANN	Benign	0.60
DEOGEN2	Benign	0.15	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.074	N
LIST_S2	Benign	0.62	T
MetaRNN	Benign	0.0026	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.20	N
PhyloP100		-0.33
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.12	N
REVEL	Benign	0.036
Sift	Benign	0.51	T
Sift4G	Benign	0.60	T
Polyphen		0.012	B
Vest4		0.079
MutPred		0.10		Gain of catalytic residue at G587 (P = 0.0059)
MVP		0.18
MPC		0.78
ClinPred		0.0032	T
GERP RS		-3.3
Varity_R		0.066
gMVP		0.74
Mutation Taster		=99/1	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: rs3218625; hg19: chr1-186643541; COSMIC: COSV66572041; COSMIC: COSV66572041;