rs4512367

Variant names:

• chr8-68015357-C-T
• rs4512367
• NM_024870.4:c.142-2489C>T

Your query was ambiguous. Multiple possible variants found:

• chr8-68015357-C-T
• chr8-68015357-C-G

Variant summary

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

The NM_024870.4(PREX2):​c.142-2489C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.433 in 152,002 control chromosomes in the GnomAD database, including 17,389 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as association (no stars).

• Frequency: Genomes: 𝑓 0.43 (17389 hom., cov: 33)
• Consequence: PREX2 NM_024870.4 intron
• Clinical Significance: association no assertion criteria provided O:1
• Conservation: PhyloP100: -0.369
• Publications: 4 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=-0.66).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.744 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024870.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PREX2	NM_024870.4	MANE Select	c.142-2489C>T		intron	N/A	NP_079146.2
	PREX2	NM_025170.6		c.142-2489C>T		intron	N/A	NP_079446.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PREX2	ENST00000288368.5	TSL:1 MANE Select	c.142-2489C>T		intron	N/A	ENSP00000288368.4	Q70Z35-1
	PREX2	ENST00000529398.5	TSL:1	n.169-2489C>T		intron	N/A
	PREX2	ENST00000854544.1		c.142-6679C>T		intron	N/A	ENSP00000524603.1

Frequencies

GnomAD3 genomes AF: 0.433 AC: 65741 AN: 151884 Hom.: 17343 Cov.: 33

Gnomad AFR AF: 0.751

Gnomad AMI AF: 0.439

Gnomad AMR AF: 0.349

Gnomad ASJ AF: 0.350

Gnomad EAS AF: 0.185

Gnomad SAS AF: 0.435

Gnomad FIN AF: 0.280

Gnomad MID AF: 0.361

Gnomad NFE AF: 0.305

Gnomad OTH AF: 0.414

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

GnomAD4 genome AF: 0.433 AC: 65845 AN: 152002 Hom.: 17389 Cov.: 33 AF XY: 0.430 AC XY: 31981 AN XY: 74290

African (AFR) AF: 0.751 AC: 31186 AN: 41502

American (AMR) AF: 0.349 AC: 5327 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.350 AC: 1213 AN: 3466

East Asian (EAS) AF: 0.185 AC: 955 AN: 5168

South Asian (SAS) AF: 0.437 AC: 2102 AN: 4810

European-Finnish (FIN) AF: 0.280 AC: 2952 AN: 10556

Middle Eastern (MID) AF: 0.367 AC: 108 AN: 294

European-Non Finnish (NFE) AF: 0.305 AC: 20723 AN: 67914

Other (OTH) AF: 0.416 AC: 880 AN: 2114

Alfa AF: 0.337 Hom.: 38729

Bravo AF: 0.449

Asia WGS AF: 0.393 AC: 1365 AN: 3476

ClinVar

ClinVar submissions

Significance: association

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	-	Lip and oral cavity carcinoma (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	9.8
DANN	Benign	0.77
PhyloP100		-0.37
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: rs4512367; hg19: chr8-68927592;