rs4729189

Variant names:

• chr7-95428647-T-A
• rs4729189
• NM_000305.3:c.75-4062A>T

Your query was ambiguous. Multiple possible variants found:

• chr7-95428647-T-A
• chr7-95428647-T-C
• chr7-95428647-T-G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000305.3(PON2):​c.75-4062A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.794 in 152,158 control chromosomes in the GnomAD database, including 48,001 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 0.79 (48001 hom., cov: 32)
• Consequence: PON2 NM_000305.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.422
• Publications: 9 publications found

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

ENSG00000233942 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.834 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000305.3. 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.75-4062A>T		intron	N/A	NP_000296.2
	PON2	NM_001018161.2		c.75-4062A>T		intron	N/A	NP_001018171.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PON2	ENST00000222572.8	TSL:1 MANE Select	c.75-4062A>T		intron	N/A	ENSP00000222572.3
	PON2	ENST00000633192.1	TSL:1	c.138-4062A>T		intron	N/A	ENSP00000488378.1
	PON2	ENST00000633531.1	TSL:1	c.75-4062A>T		intron	N/A	ENSP00000488838.1

Frequencies

GnomAD3 genomes AF: 0.794 AC: 120708 AN: 152040 Hom.: 47960 Cov.: 32

Gnomad AFR AF: 0.783

Gnomad AMI AF: 0.774

Gnomad AMR AF: 0.803

Gnomad ASJ AF: 0.745

Gnomad EAS AF: 0.823

Gnomad SAS AF: 0.855

Gnomad FIN AF: 0.851

Gnomad MID AF: 0.747

Gnomad NFE AF: 0.787

Gnomad OTH AF: 0.775

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

GnomAD4 genome AF: 0.794 AC: 120808 AN: 152158 Hom.: 48001 Cov.: 32 AF XY: 0.798 AC XY: 59386 AN XY: 74382

African (AFR) AF: 0.783 AC: 32481 AN: 41498

American (AMR) AF: 0.803 AC: 12272 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.745 AC: 2585 AN: 3472

East Asian (EAS) AF: 0.822 AC: 4258 AN: 5178

South Asian (SAS) AF: 0.856 AC: 4129 AN: 4824

European-Finnish (FIN) AF: 0.851 AC: 9007 AN: 10586

Middle Eastern (MID) AF: 0.735 AC: 216 AN: 294

European-Non Finnish (NFE) AF: 0.787 AC: 53508 AN: 67990

Other (OTH) AF: 0.778 AC: 1646 AN: 2116

Alfa AF: 0.780 Hom.: 5398

Bravo AF: 0.784

Asia WGS AF: 0.821 AC: 2854 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.41
DANN	Benign	0.32
PhyloP100		-0.42
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4729189; hg19: chr7-95057959;