Genetic Variant NM_000305.3:c.145+2177C>G (chr7-95422338-G-C) – 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.145+2177C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.07 in 152,248 control chromosomes in the GnomAD database, including 505 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 0.070 ( 505 hom., cov: 33)

Consequence

PON2
NM_000305.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.206

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:

LOC107986822 (HGNC:):

LOC107986822 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=-0.85).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.186 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
PON2	NM_000305.3 link	c.145+2177C>G	intron_variant	Intron 2 of 8	ENST00000222572.8	NP_000296.2	Q15165-2
LOC107986822	XR_007060439.1 link	n.4580G>C	non_coding_transcript_exon_variant	Exon 2 of 2
PON2	NM_001018161.2 link	c.145+2177C>G	intron_variant	Intron 2 of 8		NP_001018171.1	Q15165-3
PON2	XM_005250453.2 link	c.-34+2177C>G	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.145+2177C>G		intron_variant	Intron 2 of 8	1	NM_000305.3	ENSP00000222572.3		Q15165-2

Frequencies

GnomAD3 genomes

AF:

0.0701

AC:

10667

AN:

152128

Hom.:

506

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0174

Gnomad AMI

AF:

0.0186

Gnomad AMR

AF:

0.0711

Gnomad ASJ

AF:

0.0899

Gnomad EAS

AF:

0.196

Gnomad SAS

AF:

0.0839

Gnomad FIN

AF:

0.0630

Gnomad MID

AF:

0.0605

Gnomad NFE

AF:

0.0921

Gnomad OTH

AF:

0.0762

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.0700

AC:

10661

AN:

152248

Hom.:

505

Cov.:

AF XY:

0.0696

AC XY:

5185

AN XY:

74444

show subpopulations

African (AFR)

AF:

0.0173

AC:

721

AN:

41564

American (AMR)

AF:

0.0710

AC:

1087

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.0899

AC:

312

AN:

3472

East Asian (EAS)

AF:

0.196

AC:

1010

AN:

5166

South Asian (SAS)

AF:

0.0840

AC:

405

AN:

4822

European-Finnish (FIN)

AF:

0.0630

AC:

668

AN:

10598

Middle Eastern (MID)

AF:

0.0548

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0921

AC:

6263

AN:

68002

Other (OTH)

AF:

0.0768

AC:

162

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

507

1014

1520

2027

2534

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

128

256

384

512

640

<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:

0.0759

Hom.:

Bravo

AF:

0.0711

Asia WGS

AF:

0.127

AC:

439

AN:

3468

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

1.0

(source)

DANN

Benign

0.65

PhyloP100

-0.21

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