8-67952493-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Moderate BP6_Moderate BA1

The NM_024870.4(PREX2):c.99G>A(p.Lys33=) variant causes a synonymous change. The variant allele was found at a frequency of 0.308 in 1,607,296 control chromosomes in the GnomAD database, including 80,095 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.25 (5726 hom., cov: 32)
  • Exomes 𝑓: 0.31 (74369 hom.)
• Consequence: PREX2 NM_024870.4 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 6.00

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.31).
• BP6: Variant 8-67952493-G-A is Benign according to our data. Variant chr8-67952493-G-A is described in ClinVar as [Benign]. Clinvar id is 3060181.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.506 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PREX2	NM_024870.4	c.99G>A	p.Lys33=	synonymous_variant	1/40	ENST00000288368.5
PREX2	NM_025170.6	c.99G>A	p.Lys33=	synonymous_variant	1/24
PREX2	XM_047422268.1	c.99G>A	p.Lys33=	synonymous_variant	1/28

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PREX2	ENST00000288368.5	c.99G>A	p.Lys33=	synonymous_variant	1/40	1	NM_024870.4	P1
PREX2	ENST00000529398.5	n.126G>A		non_coding_transcript_exon_variant	1/24	1
PREX2	ENST00000517617.1	n.5G>A		non_coding_transcript_exon_variant	1/24	2

Frequencies

GnomAD3 genomes AF: 0.251 AC: 38125 AN: 151932 Hom.: 5732 Cov.: 32

Gnomad AFR AF: 0.0907

Gnomad AMI AF: 0.202

Gnomad AMR AF: 0.323

Gnomad ASJ AF: 0.239

Gnomad EAS AF: 0.522

Gnomad SAS AF: 0.401

Gnomad FIN AF: 0.255

Gnomad MID AF: 0.215

Gnomad NFE AF: 0.302

Gnomad OTH AF: 0.264

GnomAD3 exomes AF: 0.314 AC: 73677 AN: 234986 Hom.: 12430 AF XY: 0.317 AC XY: 40544 AN XY: 127760

Gnomad AFR exome AF: 0.0833

Gnomad AMR exome AF: 0.368

Gnomad ASJ exome AF: 0.229

Gnomad EAS exome AF: 0.517

Gnomad SAS exome AF: 0.381

Gnomad FIN exome AF: 0.257

Gnomad NFE exome AF: 0.297

Gnomad OTH exome AF: 0.285

GnomAD4 exome AF: 0.314 AC: 456289 AN: 1455248 Hom.: 74369 Cov.: 37 AF XY: 0.316 AC XY: 228375 AN XY: 723482

Gnomad4 AFR exome AF: 0.0791

Gnomad4 AMR exome AF: 0.363

Gnomad4 ASJ exome AF: 0.232

Gnomad4 EAS exome AF: 0.539

Gnomad4 SAS exome AF: 0.377

Gnomad4 FIN exome AF: 0.263

Gnomad4 NFE exome AF: 0.311

Gnomad4 OTH exome AF: 0.306

GnomAD4 genome AF: 0.251 AC: 38122 AN: 152048 Hom.: 5726 Cov.: 32 AF XY: 0.253 AC XY: 18806 AN XY: 74328

Gnomad4 AFR AF: 0.0905

Gnomad4 AMR AF: 0.323

Gnomad4 ASJ AF: 0.239

Gnomad4 EAS AF: 0.523

Gnomad4 SAS AF: 0.400

Gnomad4 FIN AF: 0.255

Gnomad4 NFE AF: 0.302

Gnomad4 OTH AF: 0.263

Alfa AF: 0.276 Hom.: 3189

Bravo AF: 0.251

Asia WGS AF: 0.396 AC: 1379 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

PREX2-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 18, 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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.31
Cadd	Benign	14
Dann	Uncertain	0.97

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs61753697; hg19: chr8-68864728; COSMIC: COSV55767087;