rs730365

Variant names:

• chr7-95433688-C-T
• rs730365
• NM_000305.3:c.74+1190G>A

Variant summary

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

The NM_000305.3(PON2):​c.74+1190G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.146 in 152,212 control chromosomes in the GnomAD database, including 1,927 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 0.15 (1927 hom., cov: 33)
• Consequence: PON2 NM_000305.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.349
• Publications: 13 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=-0.88).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.218 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PON2	NM_000305.3	c.74+1190G>A		intron_variant	Intron 1 of 8	ENST00000222572.8	NP_000296.2
PON2	NM_001018161.2	c.74+1190G>A		intron_variant	Intron 1 of 8		NP_001018171.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PON2	ENST00000222572.8	c.74+1190G>A		intron_variant	Intron 1 of 8	1	NM_000305.3	ENSP00000222572.3

Frequencies

GnomAD3 genomes AF: 0.146 AC: 22160 AN: 152094 Hom.: 1925 Cov.: 33

Gnomad AFR AF: 0.222

Gnomad AMI AF: 0.126

Gnomad AMR AF: 0.134

Gnomad ASJ AF: 0.198

Gnomad EAS AF: 0.0495

Gnomad SAS AF: 0.0509

Gnomad FIN AF: 0.0662

Gnomad MID AF: 0.193

Gnomad NFE AF: 0.125

Gnomad OTH AF: 0.166

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

GnomAD4 genome AF: 0.146 AC: 22184 AN: 152212 Hom.: 1927 Cov.: 33 AF XY: 0.142 AC XY: 10597 AN XY: 74420

African (AFR) AF: 0.222 AC: 9220 AN: 41522

American (AMR) AF: 0.134 AC: 2048 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.198 AC: 686 AN: 3472

East Asian (EAS) AF: 0.0496 AC: 257 AN: 5180

South Asian (SAS) AF: 0.0512 AC: 247 AN: 4826

European-Finnish (FIN) AF: 0.0662 AC: 701 AN: 10590

Middle Eastern (MID) AF: 0.207 AC: 61 AN: 294

European-Non Finnish (NFE) AF: 0.125 AC: 8501 AN: 68002

Other (OTH) AF: 0.164 AC: 348 AN: 2116

Alfa AF: 0.140 Hom.: 1214

Bravo AF: 0.158

Asia WGS AF: 0.0710 AC: 248 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	2.6
DANN	Benign	0.60
PhyloP100		0.35
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: rs730365; hg19: chr7-95063000;