8-68017871-G-A

Position:

chr8-68017871-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_024870.4(PREX2):c.167G>A(p.Cys56Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.000342 in 1,612,912 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

Frequency

Genomes: 𝑓 0.0020 ( 5 hom., cov: 32)

Exomes 𝑓: 0.00017 ( 0 hom. )

Consequence

PREX2
NM_024870.4 missense

Scores

Clinical Significance

Likely benign no assertion criteria provided B:1

Conservation

PhyloP100: 3.88

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008489221).

BP6

Variant 8-68017871-G-A is Benign according to our data. Variant chr8-68017871-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 3053706.Status of the report is no_assertion_criteria_provided, 0 stars.

BS2

High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PREX2	NM_024870.4 linkuse as main transcript	c.167G>A	p.Cys56Tyr	missense_variant	2/40	ENST00000288368.5	NP_079146.2	Q70Z35-1
PREX2	NM_025170.6 linkuse as main transcript	c.167G>A	p.Cys56Tyr	missense_variant	2/24		NP_079446.3	Q70Z35-3
PREX2	XM_047422267.1 linkuse as main transcript	c.32G>A	p.Cys11Tyr	missense_variant	2/40		XP_047278223.1
PREX2	XM_047422268.1 linkuse as main transcript	c.167G>A	p.Cys56Tyr	missense_variant	2/28		XP_047278224.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
PREX2	ENST00000288368.5 linkuse as main transcript	c.167G>A	p.Cys56Tyr	missense_variant	2/40	1	NM_024870.4	ENSP00000288368.4	Q70Z35-1
PREX2	ENST00000529398.5 linkuse as main transcript	n.194G>A		non_coding_transcript_exon_variant	2/24	1
PREX2	ENST00000517617.1 linkuse as main transcript	n.48-4165G>A		intron_variant		2

Frequencies

GnomAD3 genomes

AF:

0.00195

AC:

296

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00683

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000458

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.000433

AC:

108

AN:

249362

Hom.:

AF XY:

0.000304

AC XY:

AN XY:

134812

show subpopulations

Gnomad AFR exome

AF:

0.00626

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000178

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.000173

AC:

253

AN:

1460622

Hom.:

Cov.:

AF XY:

0.000165

AC XY:

120

AN XY:

726590

show subpopulations

Gnomad4 AFR exome

AF:

0.00613

Gnomad4 AMR exome

AF:

0.000201

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000630

Gnomad4 OTH exome

AF:

0.000481

GnomAD4 genome

AF:

0.00196

AC:

299

AN:

152290

Hom.:

Cov.:

AF XY:

0.00192

AC XY:

143

AN XY:

74462

show subpopulations

Gnomad4 AFR

AF:

0.00688

Gnomad4 AMR

AF:

0.000457

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.000372

Hom.:

Bravo

AF:

0.00216

ESP6500AA

AF:

0.00727

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000544

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

PREX2-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 14, 2019

This variant is classified as likely 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

AlphaMissense

Benign

0.084

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.36

CADD

Benign

DANN

Benign

0.44

DEOGEN2

Benign

0.054

Eigen

Benign

-0.26

Eigen_PC

Benign

0.026

FATHMM_MKL

Uncertain

0.83

LIST_S2

Benign

0.64

M_CAP

Benign

0.011

MetaRNN

Benign

0.0085

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.23

PrimateAI

Pathogenic

0.83

PROVEAN

Benign

0.010

REVEL

Benign

0.089

Sift

Benign

1.0

Sift4G

Benign

0.93

Polyphen

0.0

Vest4

0.24

MVP

0.47

MPC

0.79

ClinPred

0.019

GERP RS

5.8

Varity_R

0.14

gMVP

0.36

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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