rs7839608

chr8-68145737-C-A

Variant summary

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

The NM_024870.4(PREX2):c.4088-472C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.418 in 151,738 control chromosomes in the GnomAD database, including 14,555 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 0.42 (14555 hom., cov: 31)
• Consequence: PREX2 NM_024870.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.202

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=-0.93).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.6 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PREX2	NM_024870.4	c.4088-472C>A		intron_variant		ENST00000288368.5
PREX2	XM_047422267.1	c.3953-472C>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PREX2	ENST00000288368.5	c.4088-472C>A		intron_variant		1	NM_024870.4	P1

Frequencies

GnomAD3 genomes AF: 0.417 AC: 63279 AN: 151620 Hom.: 14526 Cov.: 31

Gnomad AFR AF: 0.606

Gnomad AMI AF: 0.447

Gnomad AMR AF: 0.331

Gnomad ASJ AF: 0.378

Gnomad EAS AF: 0.102

Gnomad SAS AF: 0.249

Gnomad FIN AF: 0.308

Gnomad MID AF: 0.306

Gnomad NFE AF: 0.378

Gnomad OTH AF: 0.395

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.418 AC: 63352 AN: 151738 Hom.: 14555 Cov.: 31 AF XY: 0.406 AC XY: 30091 AN XY: 74120

Gnomad4 AFR AF: 0.606

Gnomad4 AMR AF: 0.330

Gnomad4 ASJ AF: 0.378

Gnomad4 EAS AF: 0.102

Gnomad4 SAS AF: 0.249

Gnomad4 FIN AF: 0.308

Gnomad4 NFE AF: 0.378

Gnomad4 OTH AF: 0.391

Alfa AF: 0.378 Hom.: 14836

Bravo AF: 0.428

Asia WGS AF: 0.203 AC: 712 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
Cadd	Benign	0.61
Dann	Benign	0.37

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: rs7839608; hg19: chr8-69057972;