7-95409919-T-C

Position:

• chr7-95409919-T-C

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_000305.3(PON2):​c.677A>G​(p.Asn226Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000636 in 1,613,402 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00067 (17 hom.)
• Consequence: PON2 NM_000305.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.470

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008585423).
• BP6: Variant 7-95409919-T-C is Benign according to our data. Variant chr7-95409919-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 933154.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAdExome4 at 17 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PON2	NM_000305.3	c.677A>G	p.Asn226Ser	missense_variant	6/9	ENST00000222572.8	NP_000296.2
LOC107986822	XR_007060439.1	n.558-8397T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PON2	ENST00000222572.8	c.677A>G	p.Asn226Ser	missense_variant	6/9	1	NM_000305.3	ENSP00000222572	P1

Frequencies

GnomAD3 genomes AF: 0.000329 AC: 50 AN: 152154 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00745

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00119 AC: 298 AN: 251168 Hom.: 4 AF XY: 0.00161 AC XY: 219 AN XY: 135740

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000723

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00817

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000123

Gnomad OTH exome AF: 0.000490

GnomAD4 exome AF: 0.000668 AC: 976 AN: 1461130 Hom.: 17 Cov.: 31 AF XY: 0.000959 AC XY: 697 AN XY: 726894

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.000514

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.00967

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000396

Gnomad4 OTH exome AF: 0.000862

GnomAD4 genome AF: 0.000328 AC: 50 AN: 152272 Hom.: 0 Cov.: 32 AF XY: 0.000403 AC XY: 30 AN XY: 74458

Gnomad4 AFR AF: 0.000144

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00746

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000198 Hom.: 0

Bravo AF: 0.000181

ExAC AF: 0.00130 AC: 158

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000119

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jun 15, 2020

Variant summary: PON2 c.677A>G (p.Asn226Ser) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0012 in 251168 control chromosomes, predominantly at a frequency of 0.0082 within the South Asian subpopulation in the gnomAD database, including 4 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 410 fold of the estimated maximal expected allele frequency for a pathogenic variant in PON2 causing Early Onset Coronary Artery Disease phenotype (2e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. c.677A>G has been reported in the literature in individuals affected with Amyotrophic Lateral Sclerosis (AML). This report however, does not provide unequivocal conclusions about association of the variant with Early Onset Coronary Artery Disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.054
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	9.3
DANN	Benign	0.91
DEOGEN2	Benign	0.28	T;.;T;.
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.62
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.80	T;T;.;T
M_CAP	Benign	0.0092	T
MetaRNN	Benign	0.0086	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.96	L;.;L;.
MutationTaster	Benign	0.73	N;N;N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.8	.;N;N;.
REVEL	Benign	0.044
Sift	Benign	0.20	.;T;T;.
Sift4G	Benign	0.18	T;T;T;T
Polyphen		0.085	B;.;B;.
Vest4		0.19
MVP		0.14
MPC		0.075
ClinPred		0.0067	T
GERP RS		-1.9
Varity_R		0.061
gMVP		0.45

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs200897774; hg19: chr7-95039231;