8-68234119-T-G

Position:

• chr8-68234119-T-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_024870.4(PREX2):​c.*2741T>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.273 in 152,100 control chromosomes in the GnomAD database, including 6,186 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.27 (6186 hom., cov: 32)
  • Failed GnomAD Quality Control
• Consequence: PREX2 NM_024870.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.603

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=-0.85).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.443 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PREX2	NM_024870.4	c.*2741T>G		3_prime_UTR_variant	40/40	ENST00000288368.5
PREX2	XM_047422267.1	c.*2741T>G		3_prime_UTR_variant	40/40

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PREX2	ENST00000288368.5	c.*2741T>G		3_prime_UTR_variant	40/40	1	NM_024870.4	P1

Frequencies

GnomAD3 genomes AF: 0.273 AC: 41479 AN: 151982 Hom.: 6181 Cov.: 32

Gnomad AFR AF: 0.187

Gnomad AMI AF: 0.281

Gnomad AMR AF: 0.381

Gnomad ASJ AF: 0.314

Gnomad EAS AF: 0.395

Gnomad SAS AF: 0.460

Gnomad FIN AF: 0.227

Gnomad MID AF: 0.345

Gnomad NFE AF: 0.283

Gnomad OTH AF: 0.285

GnomAD4 exome Data not reliable, filtered out with message: AC0 AC: 0 AN: 0 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

GnomAD4 genome AF: 0.273 AC: 41504 AN: 152100 Hom.: 6186 Cov.: 32 AF XY: 0.276 AC XY: 20537 AN XY: 74352

Gnomad4 AFR AF: 0.187

Gnomad4 AMR AF: 0.382

Gnomad4 ASJ AF: 0.314

Gnomad4 EAS AF: 0.394

Gnomad4 SAS AF: 0.459

Gnomad4 FIN AF: 0.227

Gnomad4 NFE AF: 0.283

Gnomad4 OTH AF: 0.283

Alfa AF: 0.287 Hom.: 1135

Bravo AF: 0.279

Asia WGS AF: 0.410 AC: 1425 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.15
DANN	Benign	0.52

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: rs13262547; hg19: chr8-69146354;