7-95405509-A-T

Variant names:

• chr7-95405509-A-T
• rs9641164
• NM_000305.3:c.907-21T>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.907-21T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.209 in 1,605,186 control chromosomes in the GnomAD database, including 43,090 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (3616 hom., cov: 32)
  • Exomes 𝑓: 0.21 (39474 hom.)
• Consequence: PON2 NM_000305.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.77
• Publications: 11 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=-0.54).
• BP6: Variant 7-95405509-A-T is Benign according to our data. Variant chr7-95405509-A-T is described in ClinVar as Benign. ClinVar VariationId is 1237156.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.608 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PON2	NM_000305.3	c.907-21T>A		intron_variant	Intron 8 of 8	ENST00000222572.8	NP_000296.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PON2	ENST00000222572.8	c.907-21T>A		intron_variant	Intron 8 of 8	1	NM_000305.3	ENSP00000222572.3

Frequencies

GnomAD3 genomes AF: 0.183 AC: 27852 AN: 152044 Hom.: 3613 Cov.: 32

Gnomad AFR AF: 0.0634

Gnomad AMI AF: 0.139

Gnomad AMR AF: 0.334

Gnomad ASJ AF: 0.172

Gnomad EAS AF: 0.626

Gnomad SAS AF: 0.274

Gnomad FIN AF: 0.153

Gnomad MID AF: 0.174

Gnomad NFE AF: 0.188

Gnomad OTH AF: 0.201

GnomAD2 exomes AF: 0.253 AC: 62976 AN: 248664 AF XY: 0.247

Gnomad AFR exome AF: 0.0592

Gnomad AMR exome AF: 0.434

Gnomad ASJ exome AF: 0.165

Gnomad EAS exome AF: 0.635

Gnomad FIN exome AF: 0.152

Gnomad NFE exome AF: 0.188

Gnomad OTH exome AF: 0.231

GnomAD4 exome AF: 0.212 AC: 308256 AN: 1453024 Hom.: 39474 Cov.: 32 AF XY: 0.212 AC XY: 153287 AN XY: 723344

African (AFR) AF: 0.0521 AC: 1733 AN: 33252

American (AMR) AF: 0.418 AC: 18689 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.166 AC: 4343 AN: 26098

East Asian (EAS) AF: 0.668 AC: 26461 AN: 39612

South Asian (SAS) AF: 0.255 AC: 21962 AN: 86032

European-Finnish (FIN) AF: 0.154 AC: 8188 AN: 53092

Middle Eastern (MID) AF: 0.166 AC: 956 AN: 5748

European-Non Finnish (NFE) AF: 0.193 AC: 213146 AN: 1104400

Other (OTH) AF: 0.213 AC: 12778 AN: 60098

GnomAD4 genome AF: 0.183 AC: 27860 AN: 152162 Hom.: 3616 Cov.: 32 AF XY: 0.191 AC XY: 14182 AN XY: 74398

African (AFR) AF: 0.0632 AC: 2626 AN: 41538

American (AMR) AF: 0.335 AC: 5114 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.172 AC: 598 AN: 3472

East Asian (EAS) AF: 0.626 AC: 3225 AN: 5152

South Asian (SAS) AF: 0.274 AC: 1321 AN: 4818

European-Finnish (FIN) AF: 0.153 AC: 1617 AN: 10578

Middle Eastern (MID) AF: 0.167 AC: 49 AN: 294

European-Non Finnish (NFE) AF: 0.188 AC: 12754 AN: 68002

Other (OTH) AF: 0.203 AC: 429 AN: 2116

Alfa AF: 0.172 Hom.: 535

Bravo AF: 0.195

Asia WGS AF: 0.405 AC: 1407 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 20, 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	-0.54
CADD	Benign	14
DANN	Benign	0.55
PhyloP100		1.8
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs9641164; hg19: chr7-95034821; COSMIC: COSV56000899; COSMIC: COSV56000899;