rs17876183

Positions:

• chr7-95434956-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.392

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 (HGNC:):

ACMG classification

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	Protein	UniProt
PON2	NM_000305.3	c.-5G>A		5_prime_UTR_variant	1/9	ENST00000222572.8	NP_000296.2
PON2	NM_001018161.2	c.-5G>A		5_prime_UTR_variant	1/9		NP_001018171.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PON2	ENST00000222572.8	c.-5G>A		5_prime_UTR_variant	1/9	1	NM_000305.3	ENSP00000222572.3

Frequencies

GnomAD3 genomes AF: 0.0140 AC: 2131 AN: 152228 Hom.: 18 Cov.: 33

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.: 19 AF XY: 0.0124 AC XY: 803 AN XY: 64686

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.: 31 AF XY: 0.0199 AC XY: 13497 AN XY: 676860

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.: 18 Cov.: 33 AF XY: 0.0133 AC XY: 994 AN XY: 74490

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.: 5

Bravo AF: 0.0137

TwinsUK AF: 0.0189 AC: 70

ALSPAC AF: 0.0210 AC: 81

ExAC AF: 0.00739 AC: 163

Asia WGS AF: 0.00144 AC: 6 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
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. -

PON2-related disorder Benign:1

Benign, no assertion criteria provided

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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	13
DANN	Pathogenic	1.0
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.32
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.64	T
MetaRNN	Benign	0.0036	T
MetaSVM	Benign	-1.0	T
Sift4G	Benign	0.13	T
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

Other links and lift over

dbSNP: rs17876183; hg19: chr7-95064268;