7-95405463-G-C

Variant names:

• chr7-95405463-G-C
• rs7493
• NM_000305.3:c.932C>G

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.932C>G​(p.Ser311Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.254 in 1,611,536 control chromosomes in the GnomAD database, including 54,604 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.27 (5893 hom., cov: 32)
  • Exomes 𝑓: 0.25 (48711 hom.)
• Consequence: PON2 NM_000305.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 9.26
• Publications: 204 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 (MetaRNN=0.0030953884).
• BP6: Variant 7-95405463-G-C is Benign according to our data. Variant chr7-95405463-G-C is described in ClinVar as Benign. ClinVar VariationId is 7084.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.349 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.932C>G	p.Ser311Cys	missense	Exon 9 of 9	NP_000296.2
	PON2	NM_001018161.2		c.896C>G	p.Ser299Cys	missense	Exon 9 of 9	NP_001018171.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PON2	ENST00000222572.8	TSL:1 MANE Select	c.932C>G	p.Ser311Cys	missense	Exon 9 of 9	ENSP00000222572.3
	PON2	ENST00000633192.1	TSL:1	c.995C>G	p.Ser332Cys	missense	Exon 9 of 9	ENSP00000488378.1
	PON2	ENST00000633531.1	TSL:1	c.932C>G	p.Ser311Cys	missense	Exon 9 of 9	ENSP00000488838.1

Frequencies

GnomAD3 genomes AF: 0.268 AC: 40743 AN: 151836 Hom.: 5877 Cov.: 32

Gnomad AFR AF: 0.287

Gnomad AMI AF: 0.372

Gnomad AMR AF: 0.220

Gnomad ASJ AF: 0.184

Gnomad EAS AF: 0.192

Gnomad SAS AF: 0.363

Gnomad FIN AF: 0.450

Gnomad MID AF: 0.239

Gnomad NFE AF: 0.243

Gnomad OTH AF: 0.236

GnomAD2 exomes AF: 0.268 AC: 66761 AN: 249520 AF XY: 0.274

Gnomad AFR exome AF: 0.296

Gnomad AMR exome AF: 0.212

Gnomad ASJ exome AF: 0.174

Gnomad EAS exome AF: 0.189

Gnomad FIN exome AF: 0.434

Gnomad NFE exome AF: 0.245

Gnomad OTH exome AF: 0.251

GnomAD4 exome AF: 0.253 AC: 368864 AN: 1459582 Hom.: 48711 Cov.: 33 AF XY: 0.257 AC XY: 186294 AN XY: 726236

African (AFR) AF: 0.299 AC: 9996 AN: 33410

American (AMR) AF: 0.213 AC: 9538 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.177 AC: 4613 AN: 26116

East Asian (EAS) AF: 0.197 AC: 7830 AN: 39676

South Asian (SAS) AF: 0.363 AC: 31294 AN: 86202

European-Finnish (FIN) AF: 0.426 AC: 22744 AN: 53398

Middle Eastern (MID) AF: 0.246 AC: 1415 AN: 5760

European-Non Finnish (NFE) AF: 0.240 AC: 266191 AN: 1109984

Other (OTH) AF: 0.253 AC: 15243 AN: 60320

GnomAD4 genome AF: 0.268 AC: 40788 AN: 151954 Hom.: 5893 Cov.: 32 AF XY: 0.277 AC XY: 20602 AN XY: 74254

African (AFR) AF: 0.287 AC: 11907 AN: 41424

American (AMR) AF: 0.220 AC: 3360 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.184 AC: 640 AN: 3472

East Asian (EAS) AF: 0.192 AC: 991 AN: 5166

South Asian (SAS) AF: 0.364 AC: 1747 AN: 4804

European-Finnish (FIN) AF: 0.450 AC: 4730 AN: 10518

Middle Eastern (MID) AF: 0.226 AC: 66 AN: 292

European-Non Finnish (NFE) AF: 0.243 AC: 16502 AN: 67986

Other (OTH) AF: 0.240 AC: 507 AN: 2110

Alfa AF: 0.235 Hom.: 3321

Bravo AF: 0.246

TwinsUK AF: 0.241 AC: 894

ALSPAC AF: 0.245 AC: 944

ESP6500AA AF: 0.284 AC: 1250

ESP6500EA AF: 0.228 AC: 1961

ExAC AF: 0.271 AC: 32895

Asia WGS AF: 0.299 AC: 1040 AN: 3478

EpiCase AF: 0.230

EpiControl AF: 0.233

ClinVar

Significance: Benign

Submissions summary: Benign:3

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 09, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 18759523, 21303902, 19930448, 19840942, 23225229, 19540141, 9443862)

PARAOXONASE 2 POLYMORPHISM Benign:1

Jan 01, 1998

OMIM

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.34
CADD	Uncertain	24
DANN	Benign	0.96
Eigen	Benign	-0.11
Eigen_PC	Benign	0.020
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.59	T
MetaRNN	Benign	0.0031	T
MetaSVM	Benign	-0.99	T
PhyloP100		9.3
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-3.5	D
REVEL	Benign	0.18
Sift	Uncertain	0.022	D
Sift4G	Uncertain	0.052	T
Vest4		0.29
MPC		0.090
ClinPred		0.15	T
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.32
gMVP		0.65
Mutation Taster		=98/2	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: rs7493; hg19: chr7-95034775; COSMIC: COSV56000788; COSMIC: COSV56000788;