rs2299259

Variant names:

• chr7-95314085-G-A
• rs2299259
• NM_000446.7:c.370+1237C>T

Your query was ambiguous. Multiple possible variants found:

• chr7-95314085-G-A
• chr7-95314085-G-T

Variant summary

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

The NM_000446.7(PON1):​c.370+1237C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.251 in 151,806 control chromosomes in the GnomAD database, including 5,132 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 0.25 (5132 hom., cov: 31)
• Consequence: PON1 NM_000446.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.809
• Publications: 5 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.0).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.487 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PON1	NM_000446.7	c.370+1237C>T		intron_variant	Intron 4 of 8	ENST00000222381.8	NP_000437.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PON1	ENST00000222381.8	c.370+1237C>T		intron_variant	Intron 4 of 8	1	NM_000446.7	ENSP00000222381.3
PON1	ENST00000433729.1	n.*95+1237C>T		intron_variant	Intron 4 of 8	3		ENSP00000407359.1
PON1	ENST00000470502.1	n.490+1237C>T		intron_variant	Intron 3 of 3	4

Frequencies

GnomAD3 genomes AF: 0.251 AC: 38039 AN: 151686 Hom.: 5124 Cov.: 31

Gnomad AFR AF: 0.155

Gnomad AMI AF: 0.331

Gnomad AMR AF: 0.276

Gnomad ASJ AF: 0.288

Gnomad EAS AF: 0.502

Gnomad SAS AF: 0.268

Gnomad FIN AF: 0.262

Gnomad MID AF: 0.241

Gnomad NFE AF: 0.278

Gnomad OTH AF: 0.265

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

GnomAD4 genome AF: 0.251 AC: 38071 AN: 151806 Hom.: 5132 Cov.: 31 AF XY: 0.253 AC XY: 18812 AN XY: 74224

African (AFR) AF: 0.155 AC: 6412 AN: 41284

American (AMR) AF: 0.275 AC: 4208 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.288 AC: 998 AN: 3470

East Asian (EAS) AF: 0.503 AC: 2584 AN: 5140

South Asian (SAS) AF: 0.269 AC: 1294 AN: 4814

European-Finnish (FIN) AF: 0.262 AC: 2769 AN: 10558

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

European-Non Finnish (NFE) AF: 0.278 AC: 18865 AN: 67950

Other (OTH) AF: 0.272 AC: 572 AN: 2104

Alfa AF: 0.261 Hom.: 6857

Bravo AF: 0.250

Asia WGS AF: 0.398 AC: 1383 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.81
DANN	Benign	0.50
PhyloP100		-0.81
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: rs2299259; hg19: chr7-94943397;