8-68055931-C-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_024870.4(PREX2):c.1195C>A(p.Arg399=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.51 in 1,607,770 control chromosomes in the GnomAD database, including 216,429 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.59 (28181 hom., cov: 32)
  • Exomes 𝑓: 0.50 (188248 hom.)
• Consequence: PREX2 NM_024870.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.56

Genes affected

PREX2 (HGNC:22950): (phosphatidylinositol-3,4,5-trisphosphate dependent Rac exchange factor 2) The protein encoded by this gene belongs to the phosphatidylinositol 3,4,5-trisphosphate (PIP3)-dependent Rac exchanger (PREX) family, which are Dbl-type guanine-nucleotide exchange factors for Rac family small G proteins. Structural domains of this protein include the catalytic diffuse B-cell lymphoma homology and pleckstrin homology (DHPH) domain, two disheveled, EGL-10, and pleckstrin homology (DEP) domains, two PDZ domains, and a C-terminal inositol polyphosphate-4 phosphatase (IP4P) domain that is found in one of the isoforms. This protein facilitates the exchange of GDP for GTP on Rac1, allowing the GTP-bound Rac1 to activate downstream effectors. Studies also show that the pleckstrin homology domain of this protein interacts with the phosphatase and tensin homolog (PTEN) gene product to inhibit PTEN phosphatase activity, thus activating the phosphoinositide-3 kinase (PI3K) signaling pathway. Conversely, the PTEN gene product has also been shown to inhibit the GEF activity of this protein. This gene plays a role in insulin-signaling pathways, and either mutations or overexpression of this gene have been observed in some cancers. [provided by RefSeq, Apr 2016]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP6: Variant 8-68055931-C-A is Benign according to our data. Variant chr8-68055931-C-A is described in ClinVar as [Benign]. Clinvar id is 1274701.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.827 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PREX2	NM_024870.4	c.1195C>A	p.Arg399=	synonymous_variant	10/40	ENST00000288368.5
PREX2	NM_025170.6	c.1195C>A	p.Arg399=	synonymous_variant	10/24
PREX2	XM_047422267.1	c.1060C>A	p.Arg354=	synonymous_variant	10/40
PREX2	XM_047422268.1	c.1195C>A	p.Arg399=	synonymous_variant	10/28

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PREX2	ENST00000288368.5	c.1195C>A	p.Arg399=	synonymous_variant	10/40	1	NM_024870.4	P1
PREX2	ENST00000529398.5	n.1222C>A		non_coding_transcript_exon_variant	10/24	1
PREX2	ENST00000517617.1	n.906C>A		non_coding_transcript_exon_variant	8/24	2

Frequencies

GnomAD3 genomes AF: 0.588 AC: 89063 AN: 151438 Hom.: 28127 Cov.: 32

Gnomad AFR AF: 0.834

Gnomad AMI AF: 0.653

Gnomad AMR AF: 0.497

Gnomad ASJ AF: 0.435

Gnomad EAS AF: 0.250

Gnomad SAS AF: 0.509

Gnomad FIN AF: 0.603

Gnomad MID AF: 0.386

Gnomad NFE AF: 0.498

Gnomad OTH AF: 0.538

GnomAD3 exomes AF: 0.497 AC: 124000 AN: 249518 Hom.: 32821 AF XY: 0.493 AC XY: 66497 AN XY: 134812

Gnomad AFR exome AF: 0.840

Gnomad AMR exome AF: 0.443

Gnomad ASJ exome AF: 0.419

Gnomad EAS exome AF: 0.224

Gnomad SAS exome AF: 0.520

Gnomad FIN exome AF: 0.595

Gnomad NFE exome AF: 0.490

Gnomad OTH exome AF: 0.493

GnomAD4 exome AF: 0.502 AC: 731017 AN: 1456214 Hom.: 188248 Cov.: 34 AF XY: 0.501 AC XY: 363000 AN XY: 724554

Gnomad4 AFR exome AF: 0.850

Gnomad4 AMR exome AF: 0.452

Gnomad4 ASJ exome AF: 0.425

Gnomad4 EAS exome AF: 0.272

Gnomad4 SAS exome AF: 0.520

Gnomad4 FIN exome AF: 0.594

Gnomad4 NFE exome AF: 0.498

Gnomad4 OTH exome AF: 0.507

GnomAD4 genome AF: 0.588 AC: 89182 AN: 151556 Hom.: 28181 Cov.: 32 AF XY: 0.591 AC XY: 43735 AN XY: 74054

Gnomad4 AFR AF: 0.834

Gnomad4 AMR AF: 0.497

Gnomad4 ASJ AF: 0.435

Gnomad4 EAS AF: 0.250

Gnomad4 SAS AF: 0.511

Gnomad4 FIN AF: 0.603

Gnomad4 NFE AF: 0.498

Gnomad4 OTH AF: 0.540

Alfa AF: 0.510 Hom.: 20377

Bravo AF: 0.586

Asia WGS AF: 0.483 AC: 1678 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

PREX2-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 17, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Dec 12, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.16
Cadd	Benign	7.1
Dann	Benign	0.63

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.25		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.25		Position offset: 43

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1434774; hg19: chr8-68968166; COSMIC: COSV55751403;