dbSNP rs13306699: PON2:p.Ser31Phe (chr7-95424568-G-A) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4BS2

The NM_000305.3(PON2):c.92C>T(p.Ser31Phe) variant causes a missense change. The variant allele was found at a frequency of 0.0000118 in 1,612,556 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S31Y) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

PON2
NM_000305.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.13

Publications

2 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: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.28015387).

BS2

High AC in GnomAdExome4 at 17 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PON2	NM_000305.3 link	c.92C>T	p.Ser31Phe	missense_variant	Exon 2 of 9	ENST00000222572.8	NP_000296.2	Q15165-2
PON2	NM_001018161.2 link	c.92C>T	p.Ser31Phe	missense_variant	Exon 2 of 9		NP_001018171.1	Q15165-3
PON2	XM_005250453.2 link	c.-87C>T		5_prime_UTR_variant	Exon 1 of 8		XP_005250510.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PON2	ENST00000222572.8 link	c.92C>T	p.Ser31Phe	missense_variant	Exon 2 of 9	1	NM_000305.3	ENSP00000222572.3		Q15165-2

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

151868

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000319

AC:

AN:

251148

AF XY:

0.0000442

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000435

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000116

AC:

AN:

1460572

Hom.:

Cov.:

AF XY:

0.0000151

AC XY:

AN XY:

726668

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33454

American (AMR)

AF:

0.00

AC:

AN:

44704

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26122

East Asian (EAS)

AF:

0.000403

AC:

AN:

39656

South Asian (SAS)

AF:

0.00

AC:

AN:

86230

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53242

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5630

European-Non Finnish (NFE)

AF:

9.00e-7

AC:

AN:

1111196

Other (OTH)

AF:

0.00

AC:

AN:

60338

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.434

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.0000132

AC:

AN:

151984

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74276

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41434

American (AMR)

AF:

0.00

AC:

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.000386

AC:

AN:

5176

South Asian (SAS)

AF:

0.00

AC:

AN:

4802

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10532

Middle Eastern (MID)

AF:

0.00

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68000

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.0000428

Hom.:

Bravo

AF:

0.0000416

ExAC

AF:

0.0000165

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.24

CADD

Benign

(source)

DANN

Benign

0.48

DEOGEN2

Benign

0.14

T;.;T;.

Eigen

Benign

-0.34

Eigen_PC

Benign

-0.13

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.65

T;T;.;T

M_CAP

Benign

0.0068

MetaRNN

Benign

0.28

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.63

N;N;N;.

PhyloP100

4.1

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-0.92

.;N;N;.

REVEL

Benign

0.17

Sift

Benign

0.74

.;T;T;.

Sift4G

Benign

0.73

T;T;T;T

Polyphen

0.0090

B;.;B;.

Vest4

0.71

MutPred

0.51

Loss of disorder (P = 0.0024);Loss of disorder (P = 0.0024);Loss of disorder (P = 0.0024);.;

MVP

0.40

MPC

0.10

ClinPred

0.080

GERP RS

4.6

Varity_R

0.096

gMVP

0.63

Mutation Taster

=82/18

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Computational scores

Splicing

Publications

Other links and lift over