8-67952391-G-C

Position:

• chr8-67952391-G-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_024870.4(PREX2):​c.-4G>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00508 in 1,539,962 control chromosomes in the GnomAD database, including 37 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0038 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0052 (33 hom.)
• Consequence: PREX2 NM_024870.4 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.403

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.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 8-67952391-G-C is Benign according to our data. Variant chr8-67952391-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 2658641.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PREX2	NM_024870.4	c.-4G>C		5_prime_UTR_variant	1/40	ENST00000288368.5
PREX2	NM_025170.6	c.-4G>C		5_prime_UTR_variant	1/24
PREX2	XM_047422268.1	c.-4G>C		5_prime_UTR_variant	1/28

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PREX2	ENST00000288368.5	c.-4G>C		5_prime_UTR_variant	1/40	1	NM_024870.4	P1
PREX2	ENST00000529398.5	n.24G>C		non_coding_transcript_exon_variant	1/24	1

Frequencies

GnomAD3 genomes AF: 0.00385 AC: 586 AN: 152036 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.000821

Gnomad AMI AF: 0.0175

Gnomad AMR AF: 0.00308

Gnomad ASJ AF: 0.00374

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00847

Gnomad FIN AF: 0.000472

Gnomad MID AF: 0.0191

Gnomad NFE AF: 0.00613

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00423 AC: 578 AN: 136646 Hom.: 2 AF XY: 0.00495 AC XY: 368 AN XY: 74366

Gnomad AFR exome AF: 0.00116

Gnomad AMR exome AF: 0.00219

Gnomad ASJ exome AF: 0.00376

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00785

Gnomad FIN exome AF: 0.00104

Gnomad NFE exome AF: 0.00577

Gnomad OTH exome AF: 0.00465

GnomAD4 exome AF: 0.00522 AC: 7240 AN: 1387814 Hom.: 33 Cov.: 30 AF XY: 0.00543 AC XY: 3717 AN XY: 684828

Gnomad4 AFR exome AF: 0.00102

Gnomad4 AMR exome AF: 0.00223

Gnomad4 ASJ exome AF: 0.00349

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00812

Gnomad4 FIN exome AF: 0.00110

Gnomad4 NFE exome AF: 0.00560

Gnomad4 OTH exome AF: 0.00525

GnomAD4 genome AF: 0.00384 AC: 585 AN: 152148 Hom.: 4 Cov.: 32 AF XY: 0.00368 AC XY: 274 AN XY: 74398

Gnomad4 AFR AF: 0.000818

Gnomad4 AMR AF: 0.00308

Gnomad4 ASJ AF: 0.00374

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00827

Gnomad4 FIN AF: 0.000472

Gnomad4 NFE AF: 0.00614

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00389 Hom.: 2

Bravo AF: 0.00369

Asia WGS AF: 0.00289 AC: 10 AN: 3470

ClinVar

Significance: Benign/Likely 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

Feb 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). -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Nov 01, 2022

PREX2: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	18
DANN	Benign	0.89

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

LitVar

Other links and lift over

dbSNP: rs367860419; hg19: chr8-68864626;