NM_000305.3:c.443C>G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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. 14/21 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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 5.63

Publications

78 publications found

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 Gene-Disease associations (from GenCC):

amyotrophic lateral sclerosis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

PON2 links:

ENSG00000233942 (HGNC:):

ENSG00000233942 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId 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 rank	MANE	Protein	UniProt
PON2	NM_000305.3 link	c.443C>G	p.Ala148Gly	missense_variant	Exon 5 of 9	ENST00000222572.8	NP_000296.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PON2	ENST00000222572.8 link	c.443C>G	p.Ala148Gly	missense_variant	Exon 5 of 9	1	NM_000305.3	ENSP00000222572.3

Frequencies

GnomAD3 genomes

AF:

0.268

AC:

40677

AN:

151850

Hom.:

5859

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.267

AC:

67004

AN:

250886

AF XY:

0.273

show subpopulations

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 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.:

AF XY:

0.257

AC XY:

186478

AN XY:

726696

show subpopulations

African (AFR)

AF:

0.297

AC:

9931

AN:

33450

American (AMR)

AF:

0.213

AC:

9528

AN:

44690

Ashkenazi Jewish (ASJ)

AF:

0.177

AC:

4610

AN:

26114

East Asian (EAS)

AF:

0.197

AC:

7825

AN:

39666

South Asian (SAS)

AF:

0.363

AC:

31291

AN:

86222

European-Finnish (FIN)

AF:

0.426

AC:

22722

AN:

53382

Middle Eastern (MID)

AF:

0.245

AC:

1412

AN:

5758

European-Non Finnish (NFE)

AF:

0.240

AC:

266755

AN:

1111134

Other (OTH)

AF:

0.253

AC:

15243

AN:

60338

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.462

Heterozygous variant carriers

13737

27473

41210

54946

68683

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

9134

18268

27402

36536

45670

<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:

0.268

AC:

40722

AN:

151968

Hom.:

5875

Cov.:

AF XY:

0.277

AC XY:

20582

AN XY:

74274

show subpopulations

African (AFR)

AF:

0.285

AC:

11828

AN:

41434

American (AMR)

AF:

0.220

AC:

3354

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.185

AC:

640

AN:

3468

East Asian (EAS)

AF:

0.192

AC:

992

AN:

5178

South Asian (SAS)

AF:

0.364

AC:

1749

AN:

4804

European-Finnish (FIN)

AF:

0.450

AC:

4745

AN:

10550

Middle Eastern (MID)

AF:

0.231

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.243

AC:

16501

AN:

67944

Other (OTH)

AF:

0.240

AC:

506

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1466

2932

4397

5863

7329

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

416

832

1248

1664

2080

<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:

0.237

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

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jun 09, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 9329371) -

PARAOXONASE 2 POLYMORPHISM

Benign:1

Oct 01, 1997

OMIM

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.091

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.57

CADD

Benign

(source)

DANN

Benign

0.87

DEOGEN2

Benign

0.16

T;.;T;.;.;.

Eigen

Benign

-1.0

Eigen_PC

Benign

-0.85

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.13

T;T;.;T;T;T

MetaRNN

Benign

0.0021

T;T;T;T;T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

-0.34

N;.;N;.;.;.

PhyloP100

5.6

PrimateAI

Benign

0.32

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

GERP RS

2.5

Varity_R

0.057

gMVP

0.40

Mutation Taster

=99/1

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over