7-95434956-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -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. 9/11 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:3

Conservation

PhyloP100: 0.392

Publications

6 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=0.0036318302).

BP6

Variant 7-95434956-C-T is Benign according to our data. Variant chr7-95434956-C-T is described in ClinVar as Benign. ClinVar VariationId 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 2130 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000633192.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PON2	NM_000305.3	MANE Select	c.-5G>A		5_prime_UTR	Exon 1 of 9	NP_000296.2
	PON2	NM_001018161.2		c.-5G>A		5_prime_UTR	Exon 1 of 9	NP_001018171.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PON2	ENST00000633192.1	TSL:1	c.59G>A	p.Arg20His	missense	Exon 1 of 9	ENSP00000488378.1
PON2	ENST00000446142.5	TSL:1	n.-5G>A		non_coding_transcript_exon	Exon 1 of 9	ENSP00000405211.1
PON2	ENST00000455123.5	TSL:1	n.-5G>A		non_coding_transcript_exon	Exon 1 of 9	ENSP00000414515.1

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

GnomAD2 exomes

AF:

0.0122

AC:

1434

AN:

117358

AF XY:

0.0124

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 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

African (AFR)

AF:

0.00353

AC:

101

AN:

28620

American (AMR)

AF:

0.00660

AC:

228

AN:

34540

Ashkenazi Jewish (ASJ)

AF:

0.00248

AC:

AN:

24558

East Asian (EAS)

AF:

0.00

AC:

AN:

33656

South Asian (SAS)

AF:

0.00649

AC:

502

AN:

77298

European-Finnish (FIN)

AF:

0.0143

AC:

564

AN:

39348

Middle Eastern (MID)

AF:

0.00408

AC:

AN:

4416

European-Non Finnish (NFE)

AF:

0.0239

AC:

25595

AN:

1072794

Other (OTH)

AF:

0.0160

AC:

914

AN:

57112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

1498

2996

4494

5992

7490

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

972

1944

2916

3888

4860

<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:

0.0140

AC:

2130

AN:

152340

Hom.:

Cov.:

AF XY:

0.0133

AC XY:

994

AN XY:

74490

show subpopulations

African (AFR)

AF:

0.00394

AC:

164

AN:

41584

American (AMR)

AF:

0.00941

AC:

144

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00259

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5176

South Asian (SAS)

AF:

0.00538

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.0142

AC:

151

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0225

AC:

1532

AN:

68022

Other (OTH)

AF:

0.0104

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

115

230

344

459

574

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

140

<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:

0.0173

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

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

PON2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.31

BayesDel_noAF

Benign

-0.49

CADD

Benign

(source)

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

PhyloP100

0.39

Sift4G

Benign

0.13

Vest4

0.067

GERP RS

3.5

PromoterAI

-0.10

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Mutation Taster

=98/2

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over