8-68030589-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6_Very_Strong BP7

The NM_024870.4(PREX2):c.636C>T(p.Asn212=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000961 in 1,613,652 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0015 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00090 (6 hom.)
• Consequence: PREX2 NM_024870.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.34

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BP6: Variant 8-68030589-C-T is Benign according to our data. Variant chr8-68030589-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 784128.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.34 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PREX2	NM_024870.4	c.636C>T	p.Asn212=	synonymous_variant	6/40	ENST00000288368.5
PREX2	NM_025170.6	c.636C>T	p.Asn212=	synonymous_variant	6/24
PREX2	XM_047422267.1	c.501C>T	p.Asn167=	synonymous_variant	6/40
PREX2	XM_047422268.1	c.636C>T	p.Asn212=	synonymous_variant	6/28

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PREX2	ENST00000288368.5	c.636C>T	p.Asn212=	synonymous_variant	6/40	1	NM_024870.4	P1
PREX2	ENST00000529398.5	n.663C>T		non_coding_transcript_exon_variant	6/24	1
PREX2	ENST00000517617.1	n.347C>T		non_coding_transcript_exon_variant	4/24	2

Frequencies

GnomAD3 genomes AF: 0.00153 AC: 233 AN: 152146 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00130

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00655

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000882

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00115 AC: 289 AN: 250900 Hom.: 0 AF XY: 0.000959 AC XY: 130 AN XY: 135562

Gnomad AFR exome AF: 0.000800

Gnomad AMR exome AF: 0.00443

Gnomad ASJ exome AF: 0.00268

Gnomad EAS exome AF: 0.0000545

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000671

Gnomad OTH exome AF: 0.00311

GnomAD4 exome AF: 0.000902 AC: 1318 AN: 1461388 Hom.: 6 Cov.: 31 AF XY: 0.000878 AC XY: 638 AN XY: 726998

Gnomad4 AFR exome AF: 0.00144

Gnomad4 AMR exome AF: 0.00461

Gnomad4 ASJ exome AF: 0.00325

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000720

Gnomad4 OTH exome AF: 0.00257

GnomAD4 genome AF: 0.00153 AC: 233 AN: 152264 Hom.: 1 Cov.: 32 AF XY: 0.00161 AC XY: 120 AN XY: 74446

Gnomad4 AFR AF: 0.00130

Gnomad4 AMR AF: 0.00654

Gnomad4 ASJ AF: 0.00317

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000882

Gnomad4 OTH AF: 0.00332

Alfa AF: 0.00132 Hom.: 0

Bravo AF: 0.00199

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00115

EpiControl AF: 0.00113

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jun 08, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2022	PREX2: BP4, BP7 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
Cadd	Benign	3.9
Dann	Benign	0.82

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: rs148808450; hg19: chr8-68942824;