1-186674636-A-G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

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. 14/22 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 the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.014 ( 47 hom., cov: 33)
Exomes 𝑓: 0.0034 ( 104 hom. )

Consequence

PTGS2
NM_000963.4 missense

Scores

2
16

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.98
Variant links:
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]

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ACMG classification

Classification was made for transcript

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 FAILED quality control check.
BS2
High AC in GnomAd4 at 2115 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PTGS2NM_000963.4 linkc.1532T>C p.Val511Ala missense_variant Exon 10 of 10 ENST00000367468.10 NP_000954.1 P35354

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PTGS2ENST00000367468.10 linkc.1532T>C p.Val511Ala missense_variant Exon 10 of 10 1 NM_000963.4 ENSP00000356438.5 P35354

Frequencies

GnomAD3 genomes
AF:
0.0138
AC:
2103
AN:
152196
Hom.:
45
Cov.:
33
show subpopulations
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
show subpopulations
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
show subpopulations
Gnomad4 AFR exome
AF:
0.0455
AC:
1525
AN:
33480
Gnomad4 AMR exome
AF:
0.00268
AC:
120
AN:
44724
Gnomad4 ASJ exome
AF:
0.00
AC:
0
AN:
26136
Gnomad4 EAS exome
AF:
0.000151
AC:
6
AN:
39700
Gnomad4 SAS exome
AF:
0.0331
AC:
2859
AN:
86256
Gnomad4 FIN exome
AF:
0.00
AC:
0
AN:
53420
Gnomad4 NFE exome
AF:
0.0000629
AC:
70
AN:
1112010
Gnomad4 Remaining exome
AF:
0.00578
AC:
349
AN:
60396
Heterozygous variant carriers
0
270
540
811
1081
1351
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Exome Het
Exome Hom
Variant carriers
0
88
176
264
352
440
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.0139
AC:
2115
AN:
152314
Hom.:
47
Cov.:
33
AF XY:
0.0138
AC XY:
1031
AN XY:
74488
show subpopulations
Gnomad4 AFR
AF:
0.0439
AC:
0.0439301
AN:
0.0439301
Gnomad4 AMR
AF:
0.00588
AC:
0.00588005
AN:
0.00588005
Gnomad4 ASJ
AF:
0.00
AC:
0
AN:
0
Gnomad4 EAS
AF:
0.000193
AC:
0.000193125
AN:
0.000193125
Gnomad4 SAS
AF:
0.0350
AC:
0.0350041
AN:
0.0350041
Gnomad4 FIN
AF:
0.00
AC:
0
AN:
0
Gnomad4 NFE
AF:
0.000132
AC:
0.000132322
AN:
0.000132322
Gnomad4 OTH
AF:
0.00899
AC:
0.0089877
AN:
0.0089877
Heterozygous variant carriers
0
100
201
301
402
502
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Genome Het
Genome Hom
Variant carriers
0
24
48
72
96
120
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
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 v4.3

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
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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

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