rs2237582

Variant names:

• chr7-95304888-A-G
• rs2237582
• NM_000446.7:c.780+1397T>C

Variant summary

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

The NM_000446.7(PON1):​c.780+1397T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.428 in 152,000 control chromosomes in the GnomAD database, including 16,415 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 0.43 (16415 hom., cov: 32)
• Consequence: PON1 NM_000446.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.48
• Publications: 8 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=-0.93).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.686 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PON1	NM_000446.7	c.780+1397T>C		intron_variant	Intron 7 of 8	ENST00000222381.8	NP_000437.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PON1	ENST00000222381.8	c.780+1397T>C		intron_variant	Intron 7 of 8	1	NM_000446.7	ENSP00000222381.3
PON1	ENST00000433729.1	n.*505+1397T>C		intron_variant	Intron 7 of 8	3		ENSP00000407359.1

Frequencies

GnomAD3 genomes AF: 0.427 AC: 64916 AN: 151882 Hom.: 16364 Cov.: 32

Gnomad AFR AF: 0.692

Gnomad AMI AF: 0.334

Gnomad AMR AF: 0.423

Gnomad ASJ AF: 0.323

Gnomad EAS AF: 0.641

Gnomad SAS AF: 0.393

Gnomad FIN AF: 0.293

Gnomad MID AF: 0.342

Gnomad NFE AF: 0.282

Gnomad OTH AF: 0.403

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

GnomAD4 genome AF: 0.428 AC: 65031 AN: 152000 Hom.: 16415 Cov.: 32 AF XY: 0.428 AC XY: 31825 AN XY: 74314

African (AFR) AF: 0.693 AC: 28719 AN: 41456

American (AMR) AF: 0.424 AC: 6478 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.323 AC: 1119 AN: 3468

East Asian (EAS) AF: 0.641 AC: 3305 AN: 5158

South Asian (SAS) AF: 0.392 AC: 1887 AN: 4812

European-Finnish (FIN) AF: 0.293 AC: 3094 AN: 10568

Middle Eastern (MID) AF: 0.340 AC: 100 AN: 294

European-Non Finnish (NFE) AF: 0.282 AC: 19162 AN: 67942

Other (OTH) AF: 0.409 AC: 864 AN: 2112

Alfa AF: 0.319 Hom.: 9154

Bravo AF: 0.452

Asia WGS AF: 0.547 AC: 1901 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.053
DANN	Benign	0.52
PhyloP100		-2.5
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: rs2237582; hg19: chr7-94934200;