chr7-95410236-G-A

Variant names:

• chr7-95410236-G-A
• rs17876148
• NM_000305.3:c.495-135C>T

Variant summary

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

The NM_000305.3(PON2):​c.495-135C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00785 in 739,628 control chromosomes in the GnomAD database, including 238 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 0.026 (178 hom., cov: 32)
  • Exomes 𝑓: 0.0031 (60 hom.)
• Consequence: PON2 NM_000305.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.944
• Publications: 1 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=-0.85).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0884 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PON2	NM_000305.3	MANE Select	c.495-135C>T		intron	N/A	NP_000296.2
	PON2	NM_001018161.2		c.459-135C>T		intron	N/A	NP_001018171.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PON2	ENST00000222572.8	TSL:1 MANE Select	c.495-135C>T		intron	N/A	ENSP00000222572.3
	PON2	ENST00000633192.1	TSL:1	c.558-135C>T		intron	N/A	ENSP00000488378.1
	PON2	ENST00000633531.1	TSL:1	c.495-135C>T		intron	N/A	ENSP00000488838.1

Frequencies

GnomAD3 genomes AF: 0.0260 AC: 3962 AN: 152100 Hom.: 179 Cov.: 32

Gnomad AFR AF: 0.0911

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00845

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000382

Gnomad OTH AF: 0.0153

GnomAD4 exome AF: 0.00314 AC: 1842 AN: 587410 Hom.: 60 AF XY: 0.00259 AC XY: 814 AN XY: 314754

African (AFR) AF: 0.0874 AC: 1341 AN: 15350

American (AMR) AF: 0.00559 AC: 175 AN: 31298

Ashkenazi Jewish (ASJ) AF: 0.000693 AC: 13 AN: 18746

East Asian (EAS) AF: 0.00 AC: 0 AN: 31708

South Asian (SAS) AF: 0.000152 AC: 9 AN: 59214

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33108

Middle Eastern (MID) AF: 0.00407 AC: 13 AN: 3196

European-Non Finnish (NFE) AF: 0.000286 AC: 104 AN: 363690

Other (OTH) AF: 0.00601 AC: 187 AN: 31100

GnomAD4 genome AF: 0.0260 AC: 3962 AN: 152218 Hom.: 178 Cov.: 32 AF XY: 0.0240 AC XY: 1788 AN XY: 74414

African (AFR) AF: 0.0908 AC: 3772 AN: 41540

American (AMR) AF: 0.00844 AC: 129 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000382 AC: 26 AN: 68004

Other (OTH) AF: 0.0152 AC: 32 AN: 2112

Alfa AF: 0.0207 Hom.: 10

Bravo AF: 0.0295

Asia WGS AF: 0.00520 AC: 18 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	2.7
DANN	Benign	0.50
PhyloP100		0.94
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: rs17876148; hg19: chr7-95039548;