rs2299260

Variant names:

• chr7-95320225-T-C
• rs2299260
• NM_000446.7:c.75-1832A>G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

The NM_000446.7(PON1):​c.75-1832A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.22 in 152,176 control chromosomes in the GnomAD database, including 4,034 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 0.22 (4034 hom., cov: 33)
• Consequence: PON1 NM_000446.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.755
• Publications: 13 publications found

Genes affected

PON1 (HGNC:9204): (paraoxonase 1) This gene encodes a member of the paraoxonase family of enzymes and exhibits lactonase and ester hydrolase activity. Following synthesis in the kidney and liver, the enzyme is secreted into the circulation, where it binds to high density lipoprotein (HDL) particles and hydrolyzes thiolactones and xenobiotics, including paraoxon, a metabolite of the insecticide parathion. Polymorphisms in this gene may be associated with coronary artery disease and diabetic retinopathy. The gene is found in a cluster of three related paraoxonase genes on chromosome 7. [provided by RefSeq, Aug 2017]

PON1 Gene-Disease associations (from GenCC):

• amyotrophic lateral sclerosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.317 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PON1	NM_000446.7	c.75-1832A>G		intron_variant	Intron 1 of 8	ENST00000222381.8	NP_000437.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PON1	ENST00000222381.8	c.75-1832A>G		intron_variant	Intron 1 of 8	1	NM_000446.7	ENSP00000222381.3
PON1	ENST00000433729.1	n.75-1832A>G		intron_variant	Intron 1 of 8	3		ENSP00000407359.1

Frequencies

GnomAD3 genomes AF: 0.220 AC: 33443 AN: 152058 Hom.: 4029 Cov.: 33

Gnomad AFR AF: 0.321

Gnomad AMI AF: 0.183

Gnomad AMR AF: 0.139

Gnomad ASJ AF: 0.194

Gnomad EAS AF: 0.133

Gnomad SAS AF: 0.264

Gnomad FIN AF: 0.232

Gnomad MID AF: 0.203

Gnomad NFE AF: 0.181

Gnomad OTH AF: 0.199

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

GnomAD4 genome AF: 0.220 AC: 33453 AN: 152176 Hom.: 4034 Cov.: 33 AF XY: 0.218 AC XY: 16235 AN XY: 74400

African (AFR) AF: 0.321 AC: 13328 AN: 41504

American (AMR) AF: 0.139 AC: 2125 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.194 AC: 672 AN: 3472

East Asian (EAS) AF: 0.132 AC: 684 AN: 5176

South Asian (SAS) AF: 0.263 AC: 1268 AN: 4826

European-Finnish (FIN) AF: 0.232 AC: 2453 AN: 10574

Middle Eastern (MID) AF: 0.194 AC: 57 AN: 294

European-Non Finnish (NFE) AF: 0.181 AC: 12285 AN: 68006

Other (OTH) AF: 0.196 AC: 414 AN: 2114

Alfa AF: 0.190 Hom.: 9368

Bravo AF: 0.214

Asia WGS AF: 0.178 AC: 617 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	16
DANN	Benign	0.47
PhyloP100		-0.76
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.50		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.50		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2299260; hg19: chr7-94949537;