8-68017871-G-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_024870.4(PREX2):c.167G>A(p.Cys56Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.000342 in 1,612,912 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0020 (5 hom., cov: 32)
  • Exomes 𝑓: 0.00017 (0 hom.)
• Consequence: PREX2 NM_024870.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.88

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008489221).
• BP6: Variant 8-68017871-G-A is Benign according to our data. Variant chr8-68017871-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 3053706.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PREX2	NM_024870.4	c.167G>A	p.Cys56Tyr	missense_variant	2/40	ENST00000288368.5
PREX2	NM_025170.6	c.167G>A	p.Cys56Tyr	missense_variant	2/24
PREX2	XM_047422267.1	c.32G>A	p.Cys11Tyr	missense_variant	2/40
PREX2	XM_047422268.1	c.167G>A	p.Cys56Tyr	missense_variant	2/28

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PREX2	ENST00000288368.5	c.167G>A	p.Cys56Tyr	missense_variant	2/40	1	NM_024870.4	P1
PREX2	ENST00000529398.5	n.194G>A		non_coding_transcript_exon_variant	2/24	1
PREX2	ENST00000517617.1	n.48-4165G>A		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.00195 AC: 296 AN: 152172 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.00683

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.000433 AC: 108 AN: 249362 Hom.: 0 AF XY: 0.000304 AC XY: 41 AN XY: 134812

Gnomad AFR exome AF: 0.00626

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000178

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000173 AC: 253 AN: 1460622 Hom.: 0 Cov.: 30 AF XY: 0.000165 AC XY: 120 AN XY: 726590

Gnomad4 AFR exome AF: 0.00613

Gnomad4 AMR exome AF: 0.000201

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000630

Gnomad4 OTH exome AF: 0.000481

GnomAD4 genome AF: 0.00196 AC: 299 AN: 152290 Hom.: 5 Cov.: 32 AF XY: 0.00192 AC XY: 143 AN XY: 74462

Gnomad4 AFR AF: 0.00688

Gnomad4 AMR AF: 0.000457

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000372 Hom.: 2

Bravo AF: 0.00216

ESP6500AA AF: 0.00727 AC: 32

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000544 AC: 66

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

PREX2-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 14, 2019

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

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.36
Cadd	Benign	17
Dann	Benign	0.44
DEOGEN2	Benign	0.054	T
Eigen	Benign	-0.26
Eigen_PC	Benign	0.026
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.64	T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.0085	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.23	N
MutationTaster	Benign	0.99	D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	0.010	N
REVEL	Benign	0.089
Sift	Benign	1.0	T
Sift4G	Benign	0.93	T
Polyphen		0.0	B
Vest4		0.24
MVP		0.47
MPC		0.79
ClinPred		0.019	T
GERP RS		5.8
Varity_R		0.14
gMVP		0.36

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs146009571; hg19: chr8-68930106;