7-95410082-C-G

Position:

• chr7-95410082-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000305.3(PON2):​c.514G>C​(p.Val172Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00207 in 1,613,490 control chromosomes in the GnomAD database, including 58 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.011 (28 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (30 hom.)
• Consequence: PON2 NM_000305.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.548

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]

LOC107986822 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00955832).
• BP6: Variant 7-95410082-C-G is Benign according to our data. Variant chr7-95410082-C-G is described in ClinVar as [Benign]. Clinvar id is 787052.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0105 (1604/152196) while in subpopulation AFR AF= 0.0356 (1476/41518). AF 95% confidence interval is 0.034. There are 28 homozygotes in gnomad4. There are 764 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 28 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PON2	NM_000305.3	c.514G>C	p.Val172Leu	missense_variant	6/9	ENST00000222572.8	NP_000296.2
LOC107986822	XR_007060439.1	n.558-8234C>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PON2	ENST00000222572.8	c.514G>C	p.Val172Leu	missense_variant	6/9	1	NM_000305.3	ENSP00000222572	P1

Frequencies

GnomAD3 genomes AF: 0.0105 AC: 1598 AN: 152078 Hom.: 28 Cov.: 32

Gnomad AFR AF: 0.0355

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00570

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.00813

GnomAD3 exomes AF: 0.00276 AC: 692 AN: 251120 Hom.: 12 AF XY: 0.00200 AC XY: 272 AN XY: 135710

Gnomad AFR exome AF: 0.0329

Gnomad AMR exome AF: 0.00287

Gnomad ASJ exome AF: 0.00238

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000211

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.00119 AC: 1736 AN: 1461294 Hom.: 30 Cov.: 31 AF XY: 0.00100 AC XY: 729 AN XY: 726962

Gnomad4 AFR exome AF: 0.0366

Gnomad4 AMR exome AF: 0.00302

Gnomad4 ASJ exome AF: 0.00230

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000909

Gnomad4 OTH exome AF: 0.00318

GnomAD4 genome AF: 0.0105 AC: 1604 AN: 152196 Hom.: 28 Cov.: 32 AF XY: 0.0103 AC XY: 764 AN XY: 74410

Gnomad4 AFR AF: 0.0356

Gnomad4 AMR AF: 0.00569

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000191

Gnomad4 OTH AF: 0.00805

Alfa AF: 0.00187 Hom.: 3

Bravo AF: 0.0119

ESP6500AA AF: 0.0338 AC: 149

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00335 AC: 407

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000356

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	15
DANN	Benign	0.97
DEOGEN2	Benign	0.12	T;.;T;.;.
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.17
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.80	T;T;.;T;T
MetaRNN	Benign	0.0096	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	L;.;L;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.61	.;N;N;.;.
REVEL	Benign	0.12
Sift	Benign	0.38	.;T;T;.;.
Sift4G	Benign	0.37	T;T;T;T;.
Polyphen		0.0050	B;.;B;.;.
Vest4		0.16
MVP		0.43
MPC		0.094
ClinPred		0.0058	T
GERP RS		5.0
Varity_R		0.13
gMVP		0.49

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

Publications

LitVar

Other links and lift over

dbSNP: rs17876152; hg19: chr7-95039394;