rs1122053

chr8-67979655-A-Gchr8-67979655-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.141+27120A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.221 in 152,222 control chromosomes in the GnomAD database, including 4,812 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 0.22 (4812 hom., cov: 33)
• Consequence: PREX2 NM_024870.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.263

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=-0.73).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.524 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PREX2	NM_024870.4	c.141+27120A>G		intron_variant		ENST00000288368.5
PREX2	NM_025170.6	c.141+27120A>G		intron_variant
PREX2	XM_047422268.1	c.141+27120A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PREX2	ENST00000288368.5	c.141+27120A>G		intron_variant		1	NM_024870.4	P1
PREX2	ENST00000529398.5	n.168+27120A>G		intron_variant, non_coding_transcript_variant		1
PREX2	ENST00000517617.1	n.47+27120A>G		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.221 AC: 33677 AN: 152104 Hom.: 4815 Cov.: 33

Gnomad AFR AF: 0.0529

Gnomad AMI AF: 0.232

Gnomad AMR AF: 0.328

Gnomad ASJ AF: 0.221

Gnomad EAS AF: 0.541

Gnomad SAS AF: 0.376

Gnomad FIN AF: 0.234

Gnomad MID AF: 0.231

Gnomad NFE AF: 0.262

Gnomad OTH AF: 0.253

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

GnomAD4 genome AF: 0.221 AC: 33682 AN: 152222 Hom.: 4812 Cov.: 33 AF XY: 0.227 AC XY: 16923 AN XY: 74436

Gnomad4 AFR AF: 0.0528

Gnomad4 AMR AF: 0.329

Gnomad4 ASJ AF: 0.221

Gnomad4 EAS AF: 0.541

Gnomad4 SAS AF: 0.376

Gnomad4 FIN AF: 0.234

Gnomad4 NFE AF: 0.262

Gnomad4 OTH AF: 0.252

Alfa AF: 0.230 Hom.: 595

Bravo AF: 0.224

Asia WGS AF: 0.405 AC: 1407 AN: 3472

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
Cadd	Benign	12
Dann	Benign	0.63

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: rs1122053; hg19: chr8-68891890;