8-68030666-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_024870.4(PREX2):c.705+8C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000549 in 1,613,026 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0025 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00034 (3 hom.)
• Consequence: PREX2 NM_024870.4 splice_region, intron
• Scores: Splicing: ADA: 0.0002051
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.169

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BP6: Variant 8-68030666-C-T is Benign according to our data. Variant chr8-68030666-C-T is described in ClinVar as [Benign]. Clinvar id is 725836.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PREX2	NM_024870.4	c.705+8C>T		splice_region_variant, intron_variant		ENST00000288368.5
PREX2	NM_025170.6	c.705+8C>T		splice_region_variant, intron_variant
PREX2	XM_047422267.1	c.570+8C>T		splice_region_variant, intron_variant
PREX2	XM_047422268.1	c.705+8C>T		splice_region_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PREX2	ENST00000288368.5	c.705+8C>T		splice_region_variant, intron_variant		1	NM_024870.4	P1
PREX2	ENST00000529398.5	n.732+8C>T		splice_region_variant, intron_variant, non_coding_transcript_variant		1
PREX2	ENST00000517617.1	n.416+8C>T		splice_region_variant, intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.00246 AC: 374 AN: 152130 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00801

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00138

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00249

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.000778 AC: 195 AN: 250604 Hom.: 2 AF XY: 0.000687 AC XY: 93 AN XY: 135410

Gnomad AFR exome AF: 0.00745

Gnomad AMR exome AF: 0.000376

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00183

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000884

Gnomad OTH exome AF: 0.000655

GnomAD4 exome AF: 0.000344 AC: 502 AN: 1460778 Hom.: 3 Cov.: 30 AF XY: 0.000339 AC XY: 246 AN XY: 726686

Gnomad4 AFR exome AF: 0.00781

Gnomad4 AMR exome AF: 0.000492

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00184

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000720

Gnomad4 OTH exome AF: 0.000845

GnomAD4 genome AF: 0.00252 AC: 384 AN: 152248 Hom.: 1 Cov.: 32 AF XY: 0.00243 AC XY: 181 AN XY: 74440

Gnomad4 AFR AF: 0.00821

Gnomad4 AMR AF: 0.00137

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00269

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.000557 Hom.: 0

Bravo AF: 0.00262

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

PREX2-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 11, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Mar 29, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
Cadd	Benign	3.1
Dann	Benign	0.82

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00021
dbscSNV1_RF	Benign	0.014
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: rs111476269; hg19: chr8-68942901;