rs17876183

Positions:

chr7-95434956-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The ENST00000633192.1(PON2):c.59G>A(p.Arg20His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0198 in 1,524,682 control chromosomes in the GnomAD database, including 388 homozygotes. In-silico tool predicts a benign outcome for this variant. 7/9 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.014 ( 18 hom., cov: 33)

Exomes 𝑓: 0.020 ( 370 hom. )

Consequence

PON2
ENST00000633192.1 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.392

Variant links:

Genes affected

PON2 (HGNC:9205): (paraoxonase 2) This gene encodes a member of the paraoxonase gene family, which includes three known members located adjacent to each other on the long arm of chromosome 7. The encoded protein is ubiquitously expressed in human tissues, membrane-bound, and may act as a cellular antioxidant, protecting cells from oxidative stress. Hydrolytic activity against acylhomoserine lactones, important bacterial quorum-sensing mediators, suggests the encoded protein may also play a role in defense responses to pathogenic bacteria. Mutations in this gene may be associated with vascular disease and a number of quantitative phenotypes related to diabetes. Alternatively spliced transcript variants encoding different isoforms have been described. [provided by RefSeq, Jul 2008]

PON2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0036318302).

BP6

Variant 7-95434956-C-T is Benign according to our data. Variant chr7-95434956-C-T is described in ClinVar as [Benign]. Clinvar id is 495799.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.014 (2130/152340) while in subpopulation NFE AF= 0.0225 (1532/68022). AF 95% confidence interval is 0.0216. There are 18 homozygotes in gnomad4. There are 994 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 18 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PON2	NM_000305.3 linkuse as main transcript	c.-5G>A		5_prime_UTR_variant	1/9	ENST00000222572.8
PON2	NM_001018161.2 linkuse as main transcript	c.-5G>A		5_prime_UTR_variant	1/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PON2	ENST00000222572.8 linkuse as main transcript	c.-5G>A		5_prime_UTR_variant	1/9	1	NM_000305.3	P1	Q15165-2

Frequencies

GnomAD3 genomes

AF:

0.0140

AC:

2131

AN:

152228

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00396

Gnomad AMI

AF:

0.0888

Gnomad AMR

AF:

0.00942

Gnomad ASJ

AF:

0.00259

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00537

Gnomad FIN

AF:

0.0142

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0225

Gnomad OTH

AF:

0.0110

GnomAD3 exomes

AF:

0.0122

AC:

1434

AN:

117358

Hom.:

AF XY:

0.0124

AC XY:

803

AN XY:

64686

show subpopulations

Gnomad AFR exome

AF:

0.00413

Gnomad AMR exome

AF:

0.00625

Gnomad ASJ exome

AF:

0.00146

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00601

Gnomad FIN exome

AF:

0.0150

Gnomad NFE exome

AF:

0.0225

Gnomad OTH exome

AF:

0.0135

GnomAD4 exome

AF:

0.0204

AC:

27983

AN:

1372342

Hom.:

370

Cov.:

AF XY:

0.0199

AC XY:

13497

AN XY:

676860

show subpopulations

Gnomad4 AFR exome

AF:

0.00353

Gnomad4 AMR exome

AF:

0.00660

Gnomad4 ASJ exome

AF:

0.00248

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00649

Gnomad4 FIN exome

AF:

0.0143

Gnomad4 NFE exome

AF:

0.0239

Gnomad4 OTH exome

AF:

0.0160

GnomAD4 genome

AF:

0.0140

AC:

2130

AN:

152340

Hom.:

Cov.:

AF XY:

0.0133

AC XY:

994

AN XY:

74490

show subpopulations

Gnomad4 AFR

AF:

0.00394

Gnomad4 AMR

AF:

0.00941

Gnomad4 ASJ

AF:

0.00259

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00538

Gnomad4 FIN

AF:

0.0142

Gnomad4 NFE

AF:

0.0225

Gnomad4 OTH

AF:

0.0104

Alfa

AF:

0.0173

Hom.:

Bravo

AF:

0.0137

TwinsUK

AF:

0.0189

AC:

ALSPAC

AF:

0.0210

AC:

ExAC

AF:

0.00739

AC:

163

Asia WGS

AF:

0.00144

AC:

AN:

3476

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

PON2-related disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 24, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Nov 21, 2016

Variant summary: The PON2 c.-5G>A variant involves the alteration of a non-conserved nucleotide in 5-prime untranslated region. This variant was found in 99/11484 control chromosomes (including 2 homozygotes), predominantly observed in the European (Non-Finnish) subpopulation at a frequency of 0.0143312 (45/3140). This frequency is about 717 times the estimated maximal expected allele frequency of a pathogenic PON2 variant (0.00002), suggesting this is very likely a benign polymorphism found primarily in the populations of European (Non-Finnish) origin. The variant has been suggested to modestly increase risk for systemic lupus erythematosus (OR: 4.63 95% CI 1.37-15.59, P= 0.013) (Dasgupta_2011); however gene-phenotype link has not been ascertained thus needing further confirmation of the association. The variant has not been seen in patients with cardiac phenotype, to our knowledge. One internal sample screened for cardiac disease also carries LDLR p.E228X, supporting for a benign outcome. Taken together, this variant is classified as Benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.49

CADD

Benign

DANN

Pathogenic

1.0

Eigen

Benign

-0.24

Eigen_PC

Benign

-0.32

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.64

MetaRNN

Benign

0.0036

MetaSVM

Benign

-1.0

MutationTaster

Benign

1.0

D;D;N

Sift4G

Benign

0.13

Vest4

0.067

GERP RS

3.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over