chr8-68017892-A-G
Variant names:
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_024870.4(PREX2):āc.188A>Gā(p.Lys63Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000612 in 1,612,770 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ).
Frequency
Genomes: š 0.00045 ( 0 hom., cov: 32)
Exomes š: 0.00063 ( 0 hom. )
Consequence
PREX2
NM_024870.4 missense
NM_024870.4 missense
Scores
3
5
11
Clinical Significance
Conservation
PhyloP100: 7.67
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]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 0 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.16426596).
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| PREX2 | NM_024870.4 | c.188A>G | p.Lys63Arg | missense_variant | Exon 2 of 40 | ENST00000288368.5 | NP_079146.2 | |
| PREX2 | NM_025170.6 | c.188A>G | p.Lys63Arg | missense_variant | Exon 2 of 24 | NP_079446.3 | ||
| PREX2 | XM_047422267.1 | c.53A>G | p.Lys18Arg | missense_variant | Exon 2 of 40 | XP_047278223.1 | ||
| PREX2 | XM_047422268.1 | c.188A>G | p.Lys63Arg | missense_variant | Exon 2 of 28 | XP_047278224.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| PREX2 | ENST00000288368.5 | c.188A>G | p.Lys63Arg | missense_variant | Exon 2 of 40 | 1 | NM_024870.4 | ENSP00000288368.4 | ||
| PREX2 | ENST00000529398.5 | n.215A>G | non_coding_transcript_exon_variant | Exon 2 of 24 | 1 | |||||
| PREX2 | ENST00000517617.1 | n.48-4144A>G | intron_variant | Intron 1 of 23 | 2 |
Frequencies
GnomAD3 genomes 0.000447 AC: 68AN: 152180Hom.: 0 Cov.: 32
GnomAD3 genomes
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GnomAD3 exomes AF: 0.000450 AC: 112AN: 248958Hom.: 0 AF XY: 0.000416 AC XY: 56AN XY: 134586
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GnomAD4 exome AF: 0.000629 AC: 919AN: 1460472Hom.: 0 Cov.: 30 AF XY: 0.000577 AC XY: 419AN XY: 726504
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GnomAD4 genome 0.000446 AC: 68AN: 152298Hom.: 0 Cov.: 32 AF XY: 0.000416 AC XY: 31AN XY: 74468
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not specified Uncertain:1
Oct 06, 2021
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing
The c.188A>G (p.K63R) alteration is located in exon 2 (coding exon 2) of the PREX2 gene. This alteration results from a A to G substitution at nucleotide position 188, causing the lysine (K) at amino acid position 63 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Pathogenic
DEOGEN2
Benign
T
Eigen
Uncertain
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D
M_CAP
Benign
D
MetaRNN
Benign
T
MetaSVM
Uncertain
T
MutationAssessor
Benign
L
PrimateAI
Uncertain
T
PROVEAN
Benign
N
REVEL
Benign
Sift
Benign
D
Sift4G
Uncertain
D
Polyphen
D
Vest4
MVP
MPC
ClinPred
T
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gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at