chr7-95406270-A-T

Variant names:

• chr7-95406270-A-T
• rs3735586
• NM_000305.3:c.778-23T>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000305.3(PON2):​c.778-23T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.255 in 1,600,014 control chromosomes in the GnomAD database, including 54,720 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.28 (6380 hom., cov: 32)
  • Exomes 𝑓: 0.25 (48340 hom.)
• Consequence: PON2 NM_000305.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.226
• Publications: 10 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 7-95406270-A-T is Benign according to our data. Variant chr7-95406270-A-T is described in ClinVar as Benign. ClinVar VariationId is 1231210.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.351 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PON2	NM_000305.3	c.778-23T>A		intron_variant	Intron 7 of 8	ENST00000222572.8	NP_000296.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PON2	ENST00000222572.8	c.778-23T>A		intron_variant	Intron 7 of 8	1	NM_000305.3	ENSP00000222572.3

Frequencies

GnomAD3 genomes AF: 0.279 AC: 42331 AN: 151944 Hom.: 6360 Cov.: 32

Gnomad AFR AF: 0.321

Gnomad AMI AF: 0.372

Gnomad AMR AF: 0.226

Gnomad ASJ AF: 0.186

Gnomad EAS AF: 0.191

Gnomad SAS AF: 0.365

Gnomad FIN AF: 0.450

Gnomad MID AF: 0.252

Gnomad NFE AF: 0.243

Gnomad OTH AF: 0.244

GnomAD2 exomes AF: 0.270 AC: 67637 AN: 250670 AF XY: 0.275

Gnomad AFR exome AF: 0.328

Gnomad AMR exome AF: 0.215

Gnomad ASJ exome AF: 0.176

Gnomad EAS exome AF: 0.189

Gnomad FIN exome AF: 0.434

Gnomad NFE exome AF: 0.245

Gnomad OTH exome AF: 0.252

GnomAD4 exome AF: 0.253 AC: 365854 AN: 1447952 Hom.: 48340 Cov.: 31 AF XY: 0.256 AC XY: 184918 AN XY: 721134

African (AFR) AF: 0.334 AC: 11035 AN: 33088

American (AMR) AF: 0.216 AC: 9650 AN: 44650

Ashkenazi Jewish (ASJ) AF: 0.179 AC: 4651 AN: 26050

East Asian (EAS) AF: 0.197 AC: 7799 AN: 39558

South Asian (SAS) AF: 0.362 AC: 31133 AN: 85902

European-Finnish (FIN) AF: 0.426 AC: 22595 AN: 53058

Middle Eastern (MID) AF: 0.247 AC: 1413 AN: 5728

European-Non Finnish (NFE) AF: 0.238 AC: 262296 AN: 1099994

Other (OTH) AF: 0.255 AC: 15282 AN: 59924

GnomAD4 genome AF: 0.279 AC: 42386 AN: 152062 Hom.: 6380 Cov.: 32 AF XY: 0.288 AC XY: 21399 AN XY: 74336

African (AFR) AF: 0.322 AC: 13350 AN: 41472

American (AMR) AF: 0.226 AC: 3451 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.186 AC: 645 AN: 3466

East Asian (EAS) AF: 0.191 AC: 987 AN: 5174

South Asian (SAS) AF: 0.365 AC: 1756 AN: 4812

European-Finnish (FIN) AF: 0.450 AC: 4748 AN: 10554

Middle Eastern (MID) AF: 0.240 AC: 70 AN: 292

European-Non Finnish (NFE) AF: 0.243 AC: 16515 AN: 67980

Other (OTH) AF: 0.249 AC: 525 AN: 2112

Alfa AF: 0.251 Hom.: 979

Bravo AF: 0.258

Asia WGS AF: 0.303 AC: 1054 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 19, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	13
DANN	Benign	0.58
PhyloP100		0.23
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: rs3735586; hg19: chr7-95035582; COSMIC: COSV56000847; COSMIC: COSV56000847;