NM_000305.3:c.74+2269T>C

Variant names:

• chr7-95432609-A-G
• rs2299267
• NM_000305.3:c.74+2269T>C

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+2269T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.162 in 152,108 control chromosomes in the GnomAD database, including 2,204 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 0.16 (2204 hom., cov: 32)
• Consequence: PON2 NM_000305.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.516
• Publications: 18 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 (EAS) allele frequency at 95% confidence interval = 0.345 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PON2	NM_000305.3	c.74+2269T>C		intron_variant	Intron 1 of 8	ENST00000222572.8	NP_000296.2
PON2	NM_001018161.2	c.74+2269T>C		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+2269T>C		intron_variant	Intron 1 of 8	1	NM_000305.3	ENSP00000222572.3

Frequencies

GnomAD3 genomes AF: 0.162 AC: 24656 AN: 151990 Hom.: 2203 Cov.: 32

Gnomad AFR AF: 0.116

Gnomad AMI AF: 0.130

Gnomad AMR AF: 0.224

Gnomad ASJ AF: 0.159

Gnomad EAS AF: 0.359

Gnomad SAS AF: 0.217

Gnomad FIN AF: 0.130

Gnomad MID AF: 0.161

Gnomad NFE AF: 0.163

Gnomad OTH AF: 0.184

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

GnomAD4 genome AF: 0.162 AC: 24661 AN: 152108 Hom.: 2204 Cov.: 32 AF XY: 0.165 AC XY: 12250 AN XY: 74342

African (AFR) AF: 0.116 AC: 4796 AN: 41504

American (AMR) AF: 0.224 AC: 3424 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.159 AC: 553 AN: 3470

East Asian (EAS) AF: 0.359 AC: 1852 AN: 5160

South Asian (SAS) AF: 0.217 AC: 1045 AN: 4816

European-Finnish (FIN) AF: 0.130 AC: 1369 AN: 10566

Middle Eastern (MID) AF: 0.153 AC: 45 AN: 294

European-Non Finnish (NFE) AF: 0.163 AC: 11065 AN: 67996

Other (OTH) AF: 0.187 AC: 394 AN: 2112

Alfa AF: 0.165 Hom.: 4217

Bravo AF: 0.169

Asia WGS AF: 0.289 AC: 1002 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	8.0
DANN	Benign	0.59
PhyloP100		0.52
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: rs2299267; hg19: chr7-95061921;