rs1369165

Variant names:

• chr8-68152861-A-C
• rs1369165
• NM_024870.4:c.4232-4461A>C

Variant summary

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

The NM_024870.4(PREX2):​c.4232-4461A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.46 in 151,872 control chromosomes in the GnomAD database, including 16,351 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 0.46 (16351 hom., cov: 31)
• Consequence: PREX2 NM_024870.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.639
• 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 = 0.532 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PREX2	NM_024870.4	c.4232-4461A>C		intron_variant	Intron 34 of 39	ENST00000288368.5	NP_079146.2
PREX2	XM_047422267.1	c.4097-4461A>C		intron_variant	Intron 34 of 39		XP_047278223.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PREX2	ENST00000288368.5	c.4232-4461A>C		intron_variant	Intron 34 of 39	1	NM_024870.4	ENSP00000288368.4

Frequencies

GnomAD3 genomes AF: 0.460 AC: 69837 AN: 151750 Hom.: 16330 Cov.: 31

Gnomad AFR AF: 0.537

Gnomad AMI AF: 0.505

Gnomad AMR AF: 0.379

Gnomad ASJ AF: 0.456

Gnomad EAS AF: 0.308

Gnomad SAS AF: 0.409

Gnomad FIN AF: 0.397

Gnomad MID AF: 0.402

Gnomad NFE AF: 0.457

Gnomad OTH AF: 0.447

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

GnomAD4 genome AF: 0.460 AC: 69912 AN: 151872 Hom.: 16351 Cov.: 31 AF XY: 0.452 AC XY: 33561 AN XY: 74244

African (AFR) AF: 0.538 AC: 22254 AN: 41386

American (AMR) AF: 0.379 AC: 5776 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.456 AC: 1583 AN: 3472

East Asian (EAS) AF: 0.309 AC: 1589 AN: 5150

South Asian (SAS) AF: 0.409 AC: 1969 AN: 4812

European-Finnish (FIN) AF: 0.397 AC: 4194 AN: 10558

Middle Eastern (MID) AF: 0.405 AC: 119 AN: 294

European-Non Finnish (NFE) AF: 0.457 AC: 31028 AN: 67928

Other (OTH) AF: 0.446 AC: 939 AN: 2106

Alfa AF: 0.452 Hom.: 15961

Bravo AF: 0.459

Asia WGS AF: 0.370 AC: 1290 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	1.7
DANN	Benign	0.45
PhyloP100		-0.64
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: rs1369165; hg19: chr8-69065096;