Variant 8-67952493-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_ModerateBP6BA1

The NM_024870.4(PREX2):c.99G>A(p.Lys33Lys) 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 (no stars).

Frequency

Genomes: 𝑓 0.25 ( 5726 hom., cov: 32)

Exomes 𝑓: 0.31 ( 74369 hom. )

Consequence

PREX2
NM_024870.4 synonymous

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: 6.00

Variant links:

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]

PREX2 links:

PREX2 (HGNC:):

PREX2 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -11 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 no_assertion_criteria_provided, 0 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	Protein	UniProt
PREX2	NM_024870.4 linkuse as main transcript	c.99G>A	p.Lys33Lys	synonymous_variant	1/40	ENST00000288368.5	NP_079146.2	Q70Z35-1
PREX2	NM_025170.6 linkuse as main transcript	c.99G>A	p.Lys33Lys	synonymous_variant	1/24		NP_079446.3	Q70Z35-3
PREX2	XM_047422268.1 linkuse as main transcript	c.99G>A	p.Lys33Lys	synonymous_variant	1/28		XP_047278224.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
PREX2	ENST00000288368.5 linkuse as main transcript	c.99G>A	p.Lys33Lys	synonymous_variant	1/40	1	NM_024870.4	ENSP00000288368.4	Q70Z35-1
PREX2	ENST00000529398.5 linkuse as main transcript	n.126G>A		non_coding_transcript_exon_variant	1/24	1
PREX2	ENST00000517617.1 linkuse as main transcript	n.5G>A		non_coding_transcript_exon_variant	1/24	2

Frequencies

GnomAD3 genomes

AF:

0.251

AC:

38125

AN:

151932

Hom.:

5732

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.316

AC XY:

228375

AN XY:

723482

show subpopulations

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.:

AF XY:

0.253

AC XY:

18806

AN XY:

74328

show subpopulations

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: no assertion criteria provided

LINK: link

Submissions by phenotype

PREX2-related disorder

Benign:1

Benign, no assertion criteria provided

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over