NM_000963.4:c.1209T>C

Variant names:

• chr1-186675946-A-G
• rs5279
• NM_000963.4:c.1209T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000963.4(PTGS2):​c.1209T>C​(p.His403His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0032 in 1,613,926 control chromosomes in the GnomAD database, including 150 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.017 (80 hom., cov: 33)
  • Exomes 𝑓: 0.0017 (70 hom.)
• Consequence: PTGS2 NM_000963.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.181
• Publications: 12 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 1-186675946-A-G is Benign according to our data. Variant chr1-186675946-A-G is described in ClinVar as Benign. ClinVar VariationId is 780290.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.181 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.057 is higher than 0.05.

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.1209T>C	p.His403His	synonymous	Exon 8 of 10	NP_000954.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTGS2	ENST00000367468.10	TSL:1 MANE Select	c.1209T>C	p.His403His	synonymous	Exon 8 of 10	ENSP00000356438.5
	PTGS2	ENST00000490885.6	TSL:1	n.1624T>C		non_coding_transcript_exon	Exon 7 of 9
	PTGS2	ENST00000559627.1	TSL:1	n.*607T>C		non_coding_transcript_exon	Exon 8 of 10	ENSP00000454130.1

Frequencies

GnomAD3 genomes AF: 0.0171 AC: 2604 AN: 152150 Hom.: 80 Cov.: 33

Gnomad AFR AF: 0.0590

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00733

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.0153

GnomAD2 exomes AF: 0.00450 AC: 1131 AN: 251236 AF XY: 0.00314

Gnomad AFR exome AF: 0.0609

Gnomad AMR exome AF: 0.00307

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000132

Gnomad OTH exome AF: 0.00294

GnomAD4 exome AF: 0.00175 AC: 2556 AN: 1461658 Hom.: 70 Cov.: 31 AF XY: 0.00145 AC XY: 1051 AN XY: 727148

African (AFR) AF: 0.0601 AC: 2012 AN: 33466

American (AMR) AF: 0.00360 AC: 161 AN: 44682

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39672

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86234

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00260 AC: 15 AN: 5768

European-Non Finnish (NFE) AF: 0.0000800 AC: 89 AN: 1111910

Other (OTH) AF: 0.00454 AC: 274 AN: 60382

GnomAD4 genome AF: 0.0171 AC: 2605 AN: 152268 Hom.: 80 Cov.: 33 AF XY: 0.0165 AC XY: 1231 AN XY: 74440

African (AFR) AF: 0.0589 AC: 2448 AN: 41546

American (AMR) AF: 0.00732 AC: 112 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 68022

Other (OTH) AF: 0.0151 AC: 32 AN: 2116

Alfa AF: 0.00867 Hom.: 25

Bravo AF: 0.0204

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000178

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	1.2
DANN	Benign	0.46
PhyloP100		-0.18
Mutation Taster		=96/4	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs5279; hg19: chr1-186645078;