rs12026

Positions:

• chr7-95411704-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000305.3(PON2):​c.443C>G​(p.Ala148Gly) variant causes a missense change. The variant allele was found at a frequency of 0.254 in 1,612,722 control chromosomes in the GnomAD database, including 54,593 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.27 (5875 hom., cov: 32)
  • Exomes 𝑓: 0.25 (48718 hom.)
• Consequence: PON2 NM_000305.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 5.63

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]

LOC107986822 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0020661056).
• BP6: Variant 7-95411704-G-C is Benign according to our data. Variant chr7-95411704-G-C is described in ClinVar as [Benign]. Clinvar id is 7085.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.35 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PON2	NM_000305.3	c.443C>G	p.Ala148Gly	missense_variant	5/9	ENST00000222572.8	NP_000296.2
LOC107986822	XR_007060439.1	n.558-6612G>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PON2	ENST00000222572.8	c.443C>G	p.Ala148Gly	missense_variant	5/9	1	NM_000305.3	ENSP00000222572	P1

Frequencies

GnomAD3 genomes AF: 0.268 AC: 40677 AN: 151850 Hom.: 5859 Cov.: 32

Gnomad AFR AF: 0.285

Gnomad AMI AF: 0.372

Gnomad AMR AF: 0.220

Gnomad ASJ AF: 0.185

Gnomad EAS AF: 0.192

Gnomad SAS AF: 0.364

Gnomad FIN AF: 0.450

Gnomad MID AF: 0.244

Gnomad NFE AF: 0.243

Gnomad OTH AF: 0.236

GnomAD3 exomes AF: 0.267 AC: 67004 AN: 250886 Hom.: 9607 AF XY: 0.273 AC XY: 37046 AN XY: 135602

Gnomad AFR exome AF: 0.294

Gnomad AMR exome AF: 0.212

Gnomad ASJ exome AF: 0.174

Gnomad EAS exome AF: 0.189

Gnomad SAS exome AF: 0.363

Gnomad FIN exome AF: 0.434

Gnomad NFE exome AF: 0.244

Gnomad OTH exome AF: 0.251

GnomAD4 exome AF: 0.253 AC: 369317 AN: 1460754 Hom.: 48718 Cov.: 34 AF XY: 0.257 AC XY: 186478 AN XY: 726696

Gnomad4 AFR exome AF: 0.297

Gnomad4 AMR exome AF: 0.213

Gnomad4 ASJ exome AF: 0.177

Gnomad4 EAS exome AF: 0.197

Gnomad4 SAS exome AF: 0.363

Gnomad4 FIN exome AF: 0.426

Gnomad4 NFE exome AF: 0.240

Gnomad4 OTH exome AF: 0.253

GnomAD4 genome AF: 0.268 AC: 40722 AN: 151968 Hom.: 5875 Cov.: 32 AF XY: 0.277 AC XY: 20582 AN XY: 74274

Gnomad4 AFR AF: 0.285

Gnomad4 AMR AF: 0.220

Gnomad4 ASJ AF: 0.185

Gnomad4 EAS AF: 0.192

Gnomad4 SAS AF: 0.364

Gnomad4 FIN AF: 0.450

Gnomad4 NFE AF: 0.243

Gnomad4 OTH AF: 0.240

Alfa AF: 0.237 Hom.: 3382

Bravo AF: 0.246

TwinsUK AF: 0.241 AC: 895

ALSPAC AF: 0.244 AC: 941

ESP6500AA AF: 0.282 AC: 1243

ESP6500EA AF: 0.228 AC: 1960

ExAC AF: 0.271 AC: 32844

Asia WGS AF: 0.299 AC: 1040 AN: 3478

EpiCase AF: 0.230

EpiControl AF: 0.233

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	GeneDx	Jun 09, 2021	This variant is associated with the following publications: (PMID: 9329371) -

PARAOXONASE 2 POLYMORPHISM Benign:1

Benign, no assertion criteria provided

literature only

OMIM

Oct 01, 1997

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	21
DANN	Benign	0.87
DEOGEN2	Benign	0.16	T;.;T;.;.;.
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.85
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.13	T;T;.;T;T;T
MetaRNN	Benign	0.0021	T;T;T;T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-0.34	N;.;N;.;.;.
MutationTaster	Benign	0.98	P;P;P
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.79	.;N;N;.;.;.
REVEL	Benign	0.12
Sift	Benign	0.030	.;D;D;.;.;.
Sift4G	Uncertain	0.056	T;T;T;T;.;T
Polyphen		0.0090	B;.;B;.;.;.
Vest4		0.063
MPC		0.092
ClinPred		0.014	T
GERP RS		2.5
Varity_R		0.057
gMVP		0.40

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

Publications

LitVar

Other links and lift over

dbSNP: rs12026; hg19: chr7-95041016; COSMIC: COSV56001217; COSMIC: COSV56001217;