rs12704795

Variant names:

• chr7-95424695-T-G
• rs12704795
• NM_000305.3:c.75-110A>C

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.75-110A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.356 in 780,832 control chromosomes in the GnomAD database, including 54,955 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.34 (9481 hom., cov: 32)
  • Exomes 𝑓: 0.36 (45474 hom.)
• Consequence: PON2 NM_000305.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0850
• Publications: 8 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=-0.87).
• BP6: Variant 7-95424695-T-G is Benign according to our data. Variant chr7-95424695-T-G is described in ClinVar as Benign. ClinVar VariationId is 1259983.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.422 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PON2	NM_000305.3	c.75-110A>C		intron_variant	Intron 1 of 8	ENST00000222572.8	NP_000296.2
PON2	NM_001018161.2	c.75-110A>C		intron_variant	Intron 1 of 8		NP_001018171.1
PON2	XM_005250453.2	c.-214A>C		upstream_gene_variant			XP_005250510.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PON2	ENST00000222572.8	c.75-110A>C		intron_variant	Intron 1 of 8	1	NM_000305.3	ENSP00000222572.3

Frequencies

GnomAD3 genomes AF: 0.337 AC: 51097 AN: 151780 Hom.: 9482 Cov.: 32

Gnomad AFR AF: 0.264

Gnomad AMI AF: 0.368

Gnomad AMR AF: 0.286

Gnomad ASJ AF: 0.473

Gnomad EAS AF: 0.00540

Gnomad SAS AF: 0.237

Gnomad FIN AF: 0.271

Gnomad MID AF: 0.443

Gnomad NFE AF: 0.426

Gnomad OTH AF: 0.365

GnomAD4 exome AF: 0.361 AC: 226797 AN: 628934 Hom.: 45474 AF XY: 0.359 AC XY: 120411 AN XY: 335524

African (AFR) AF: 0.258 AC: 4100 AN: 15862

American (AMR) AF: 0.224 AC: 6677 AN: 29848

Ashkenazi Jewish (ASJ) AF: 0.475 AC: 9327 AN: 19632

East Asian (EAS) AF: 0.00331 AC: 108 AN: 32664

South Asian (SAS) AF: 0.254 AC: 15196 AN: 59774

European-Finnish (FIN) AF: 0.287 AC: 10287 AN: 35872

Middle Eastern (MID) AF: 0.411 AC: 1010 AN: 2458

European-Non Finnish (NFE) AF: 0.420 AC: 168312 AN: 400366

Other (OTH) AF: 0.363 AC: 11780 AN: 32458

GnomAD4 genome AF: 0.336 AC: 51110 AN: 151898 Hom.: 9481 Cov.: 32 AF XY: 0.325 AC XY: 24094 AN XY: 74230

African (AFR) AF: 0.264 AC: 10930 AN: 41414

American (AMR) AF: 0.286 AC: 4361 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.473 AC: 1643 AN: 3470

East Asian (EAS) AF: 0.00541 AC: 28 AN: 5172

South Asian (SAS) AF: 0.238 AC: 1144 AN: 4810

European-Finnish (FIN) AF: 0.271 AC: 2846 AN: 10516

Middle Eastern (MID) AF: 0.462 AC: 135 AN: 292

European-Non Finnish (NFE) AF: 0.426 AC: 28926 AN: 67936

Other (OTH) AF: 0.362 AC: 763 AN: 2110

Alfa AF: 0.400 Hom.: 15930

Bravo AF: 0.332

Asia WGS AF: 0.116 AC: 408 AN: 3470

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	-0.87
CADD	Benign	2.7
DANN	Benign	0.55
PhyloP100		-0.085
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: rs12704795; hg19: chr7-95054007;