8-68046923-A-T

Position:

• chr8-68046923-A-T

Variant summary

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

The NM_024870.4(PREX2):​c.943+2333A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.588 in 151,780 control chromosomes in the GnomAD database, including 28,188 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 0.59 (28188 hom., cov: 31)
• Consequence: PREX2 NM_024870.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.327

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=-0.97).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.826 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PREX2	NM_024870.4	c.943+2333A>T		intron_variant		ENST00000288368.5	NP_079146.2
PREX2	NM_025170.6	c.943+2333A>T		intron_variant			NP_079446.3
PREX2	XM_047422267.1	c.808+2333A>T		intron_variant			XP_047278223.1
PREX2	XM_047422268.1	c.943+2333A>T		intron_variant			XP_047278224.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PREX2	ENST00000288368.5	c.943+2333A>T		intron_variant		1	NM_024870.4	ENSP00000288368	P1
PREX2	ENST00000529398.5	n.970+2333A>T		intron_variant, non_coding_transcript_variant		1
PREX2	ENST00000517617.1	n.654+2333A>T		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.588 AC: 89118 AN: 151662 Hom.: 28132 Cov.: 31

Gnomad AFR AF: 0.833

Gnomad AMI AF: 0.654

Gnomad AMR AF: 0.501

Gnomad ASJ AF: 0.434

Gnomad EAS AF: 0.249

Gnomad SAS AF: 0.496

Gnomad FIN AF: 0.585

Gnomad MID AF: 0.389

Gnomad NFE AF: 0.500

Gnomad OTH AF: 0.539

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

GnomAD4 genome AF: 0.588 AC: 89239 AN: 151780 Hom.: 28188 Cov.: 31 AF XY: 0.589 AC XY: 43710 AN XY: 74190

Gnomad4 AFR AF: 0.833

Gnomad4 AMR AF: 0.501

Gnomad4 ASJ AF: 0.434

Gnomad4 EAS AF: 0.249

Gnomad4 SAS AF: 0.499

Gnomad4 FIN AF: 0.585

Gnomad4 NFE AF: 0.500

Gnomad4 OTH AF: 0.541

Alfa AF: 0.556 Hom.: 3089

Bravo AF: 0.586

Asia WGS AF: 0.478 AC: 1662 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.88
DANN	Benign	0.62

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: rs2053140; hg19: chr8-68959158;