1-186674636-A-G

Variant names:

• chr1-186674636-A-G
• rs5273
• NM_000963.4:c.1532T>C

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.1532T>C​(p.Val511Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00438 in 1,614,204 control chromosomes in the GnomAD database, including 151 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 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 0.014 (47 hom., cov: 33)
  • Exomes 𝑓: 0.0034 (104 hom.)
• Consequence: PTGS2 NM_000963.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.98
• Publications: 34 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=0.008879662).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0139 (2115/152314) while in subpopulation AFR AF = 0.0439 (1826/41566). AF 95% confidence interval is 0.0423. There are 47 homozygotes in GnomAd4. There are 1031 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2115 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTGS2	NM_000963.4	MANE Select	c.1532T>C	p.Val511Ala	missense	Exon 10 of 10	NP_000954.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTGS2	ENST00000367468.10	TSL:1 MANE Select	c.1532T>C	p.Val511Ala	missense	Exon 10 of 10	ENSP00000356438.5
	PTGS2	ENST00000490885.6	TSL:1	n.1947T>C		non_coding_transcript_exon	Exon 9 of 9
	PTGS2	ENST00000559627.1	TSL:1	n.*930T>C		non_coding_transcript_exon	Exon 10 of 10	ENSP00000454130.1

Frequencies

GnomAD3 genomes AF: 0.0138 AC: 2103 AN: 152196 Hom.: 45 Cov.: 33

Gnomad AFR AF: 0.0438

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00589

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0350

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00908

GnomAD2 exomes AF: 0.00762 AC: 1915 AN: 251462 AF XY: 0.00802

Gnomad AFR exome AF: 0.0456

Gnomad AMR exome AF: 0.00260

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000158

Gnomad OTH exome AF: 0.00505

GnomAD4 exome AF: 0.00339 AC: 4955 AN: 1461890 Hom.: 104 Cov.: 31 AF XY: 0.00417 AC XY: 3029 AN XY: 727246

African (AFR) AF: 0.0455 AC: 1525 AN: 33480

American (AMR) AF: 0.00268 AC: 120 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.000151 AC: 6 AN: 39700

South Asian (SAS) AF: 0.0331 AC: 2859 AN: 86256

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

Middle Eastern (MID) AF: 0.00451 AC: 26 AN: 5768

European-Non Finnish (NFE) AF: 0.0000629 AC: 70 AN: 1112010

Other (OTH) AF: 0.00578 AC: 349 AN: 60396

GnomAD4 genome AF: 0.0139 AC: 2115 AN: 152314 Hom.: 47 Cov.: 33 AF XY: 0.0138 AC XY: 1031 AN XY: 74488

African (AFR) AF: 0.0439 AC: 1826 AN: 41566

American (AMR) AF: 0.00588 AC: 90 AN: 15306

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

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5178

South Asian (SAS) AF: 0.0350 AC: 169 AN: 4828

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

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68016

Other (OTH) AF: 0.00899 AC: 19 AN: 2114

Alfa AF: 0.00450 Hom.: 63

Bravo AF: 0.0147

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0447 AC: 197

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.00922 AC: 1119

Asia WGS AF: 0.0230 AC: 79 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Benign	0.31	T
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.35
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.70	T
MetaRNN	Benign	0.0089	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N
PhyloP100		6.0
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.16
Sift	Benign	0.093	T
Sift4G	Benign	0.10	T
Polyphen		0.0	B
Vest4		0.11
MVP		0.47
MPC		0.79
ClinPred		0.037	T
GERP RS		3.3
Varity_R		0.27
gMVP		0.77
Mutation Taster		=83/17	polymorphism (auto)

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: rs5273; hg19: chr1-186643768; COSMIC: COSV107473103; COSMIC: COSV107473103;