Genetic Variant NM_000305.3:c.146-2221G>A (chr7-95418518-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_000305.3(PON2):c.146-2221G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.308 in 152,068 control chromosomes in the GnomAD database, including 8,564 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.31 ( 8564 hom., cov: 32)

Exomes 𝑓: 0.50 ( 0 hom. )

Consequence

PON2
NM_000305.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0380

Publications

9 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 -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.87).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.422 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
PON2	NM_000305.3 link	c.146-2221G>A	intron_variant	Intron 2 of 8	ENST00000222572.8	NP_000296.2	Q15165-2
LOC107986822	XR_007060439.1 link	n.760C>T	non_coding_transcript_exon_variant	Exon 2 of 2
PON2	NM_001018161.2 link	c.146-2221G>A	intron_variant	Intron 2 of 8		NP_001018171.1	Q15165-3
PON2	XM_005250453.2 link	c.-33-2221G>A	intron_variant	Intron 1 of 7		XP_005250510.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PON2	ENST00000222572.8 link	c.146-2221G>A		intron_variant	Intron 2 of 8	1	NM_000305.3	ENSP00000222572.3		Q15165-2

Frequencies

GnomAD3 genomes

AF:

0.308

AC:

46765

AN:

151948

Hom.:

8565

Cov.:

show subpopulations

Gnomad AFR

AF:

0.165

Gnomad AMI

AF:

0.368

Gnomad AMR

AF:

0.273

Gnomad ASJ

AF:

0.471

Gnomad EAS

AF:

0.00559

Gnomad SAS

AF:

0.232

Gnomad FIN

AF:

0.270

Gnomad MID

AF:

0.430

Gnomad NFE

AF:

0.426

Gnomad OTH

AF:

0.346

GnomAD4 exome

AF:

0.500

AC:

AN:

Hom.:

AC XY:

AN XY:

show subpopulations

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.500

AC:

AN:

Other (OTH)

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.825

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.308

AC:

46762

AN:

152066

Hom.:

8564

Cov.:

AF XY:

0.297

AC XY:

22103

AN XY:

74336

show subpopulations

African (AFR)

AF:

0.165

AC:

6835

AN:

41490

American (AMR)

AF:

0.273

AC:

4165

AN:

15264

Ashkenazi Jewish (ASJ)

AF:

0.471

AC:

1637

AN:

3472

East Asian (EAS)

AF:

0.00560

AC:

AN:

5174

South Asian (SAS)

AF:

0.233

AC:

1124

AN:

4818

European-Finnish (FIN)

AF:

0.270

AC:

2852

AN:

10568

Middle Eastern (MID)

AF:

0.446

AC:

131

AN:

294

European-Non Finnish (NFE)

AF:

0.426

AC:

28931

AN:

67970

Other (OTH)

AF:

0.343

AC:

723

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1552

3105

4657

6210

7762

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

466

932

1398

1864

2330

<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:

0.391

Hom.:

25358

Bravo

AF:

0.300

Asia WGS

AF:

0.106

AC:

372

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

3.0

(source)

DANN

Benign

0.23

PhyloP100

0.038

Mutation Taster

=100/0

polymorphism (auto)

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over