7-95410026-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000305.3(PON2):c.570A>C(p.Leu190Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,420 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PON2 NM_000305.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.620

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.34376872).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PON2	NM_000305.3	c.570A>C	p.Leu190Phe	missense_variant	6/9	ENST00000222572.8
LOC107986822	XR_007060439.1	n.558-8290T>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PON2	ENST00000222572.8	c.570A>C	p.Leu190Phe	missense_variant	6/9	1	NM_000305.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461420 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727030

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 05, 2022

The c.570A>C (p.L190F) alteration is located in exon 6 (coding exon 6) of the PON2 gene. This alteration results from a A to C substitution at nucleotide position 570, causing the leucine (L) at amino acid position 190 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.073	T
BayesDel_noAF	Benign	-0.34
Cadd	Benign	19
Dann	Uncertain	0.99
DEOGEN2	Benign	0.29	T;.;T;.;.
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.21
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.76	T;T;.;T;T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.34	T;T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.2	L;.;L;.;.
MutationTaster	Benign	0.99	D;D;D
PrimateAI	Uncertain	0.58	T
Sift4G	Uncertain	0.0080	D;D;D;D;.
Polyphen		0.63	P;.;P;.;.
Vest4		0.54
MutPred		0.61		Gain of methylation at K191 (P = 0.0517);.;Gain of methylation at K191 (P = 0.0517);.;.;
MVP		0.46
MPC		0.17
ClinPred		0.96	D
GERP RS		1.3
Varity_R		0.42
gMVP		0.47

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-95039338;