rs2299263

Variant names:

• chr7-95411099-C-T
• rs2299263
• NM_000305.3:c.494+554G>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.494+554G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.268 in 151,940 control chromosomes in the GnomAD database, including 5,865 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 0.27 (5865 hom., cov: 32)
• Consequence: PON2 NM_000305.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.172
• 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=-0.89).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.349 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PON2	NM_000305.3	MANE Select	c.494+554G>A		intron	N/A	NP_000296.2	Q15165-2
	PON2	NM_001018161.2		c.458+554G>A		intron	N/A	NP_001018171.1	Q15165-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PON2	ENST00000222572.8	TSL:1 MANE Select	c.494+554G>A		intron	N/A	ENSP00000222572.3	Q15165-2
	PON2	ENST00000633192.1	TSL:1	c.557+554G>A		intron	N/A	ENSP00000488378.1	A0A0J9YXF2
	PON2	ENST00000633531.1	TSL:1	c.494+554G>A		intron	N/A	ENSP00000488838.1	Q15165-2

Frequencies

GnomAD3 genomes AF: 0.268 AC: 40652 AN: 151820 Hom.: 5848 Cov.: 32

Gnomad AFR AF: 0.285

Gnomad AMI AF: 0.368

Gnomad AMR AF: 0.220

Gnomad ASJ AF: 0.184

Gnomad EAS AF: 0.192

Gnomad SAS AF: 0.363

Gnomad FIN AF: 0.449

Gnomad MID AF: 0.244

Gnomad NFE AF: 0.243

Gnomad OTH AF: 0.235

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

GnomAD4 genome AF: 0.268 AC: 40699 AN: 151940 Hom.: 5865 Cov.: 32 AF XY: 0.277 AC XY: 20567 AN XY: 74238

African (AFR) AF: 0.286 AC: 11830 AN: 41432

American (AMR) AF: 0.220 AC: 3355 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.184 AC: 639 AN: 3468

East Asian (EAS) AF: 0.192 AC: 989 AN: 5162

South Asian (SAS) AF: 0.363 AC: 1744 AN: 4800

European-Finnish (FIN) AF: 0.449 AC: 4731 AN: 10530

Middle Eastern (MID) AF: 0.231 AC: 68 AN: 294

European-Non Finnish (NFE) AF: 0.243 AC: 16506 AN: 67964

Other (OTH) AF: 0.239 AC: 504 AN: 2110

Alfa AF: 0.248 Hom.: 1519

Bravo AF: 0.246

Asia WGS AF: 0.300 AC: 1041 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	4.0
DANN	Benign	0.34
PhyloP100		0.17
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: rs2299263; hg19: chr7-95040411;