chr8-68165516-C-A

Variant names:

• chr8-68165516-C-A
• rs874805
• NM_024870.4:c.4346+8080C>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_024870.4(PREX2):​c.4346+8080C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.479 in 151,752 control chromosomes in the GnomAD database, including 18,044 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 0.48 (18044 hom., cov: 30)
• Consequence: PREX2 NM_024870.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.305
• Publications: 2 publications found

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

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.614 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PREX2	NM_024870.4	c.4346+8080C>A		intron_variant	Intron 35 of 39	ENST00000288368.5	NP_079146.2
PREX2	XM_047422267.1	c.4211+8080C>A		intron_variant	Intron 35 of 39		XP_047278223.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PREX2	ENST00000288368.5	c.4346+8080C>A		intron_variant	Intron 35 of 39	1	NM_024870.4	ENSP00000288368.4
PREX2	ENST00000520235.1	n.30+8080C>A		intron_variant	Intron 1 of 4	3
PREX2	ENST00000522247.5	n.62+8080C>A		intron_variant	Intron 1 of 2	3

Frequencies

GnomAD3 genomes AF: 0.479 AC: 72615 AN: 151634 Hom.: 18010 Cov.: 30

Gnomad AFR AF: 0.620

Gnomad AMI AF: 0.498

Gnomad AMR AF: 0.375

Gnomad ASJ AF: 0.450

Gnomad EAS AF: 0.371

Gnomad SAS AF: 0.396

Gnomad FIN AF: 0.372

Gnomad MID AF: 0.398

Gnomad NFE AF: 0.449

Gnomad OTH AF: 0.457

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

GnomAD4 genome AF: 0.479 AC: 72705 AN: 151752 Hom.: 18044 Cov.: 30 AF XY: 0.470 AC XY: 34831 AN XY: 74146

African (AFR) AF: 0.621 AC: 25663 AN: 41340

American (AMR) AF: 0.375 AC: 5717 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.450 AC: 1559 AN: 3462

East Asian (EAS) AF: 0.371 AC: 1902 AN: 5128

South Asian (SAS) AF: 0.397 AC: 1906 AN: 4802

European-Finnish (FIN) AF: 0.372 AC: 3920 AN: 10528

Middle Eastern (MID) AF: 0.397 AC: 116 AN: 292

European-Non Finnish (NFE) AF: 0.449 AC: 30499 AN: 67930

Other (OTH) AF: 0.459 AC: 969 AN: 2112

Alfa AF: 0.454 Hom.: 67454

Bravo AF: 0.484

Asia WGS AF: 0.402 AC: 1401 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	3.3
DANN	Benign	0.73
PhyloP100		0.30
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs874805; hg19: chr8-69077751;