8-68118578-GCC-TCG

Variant names:

• chr8-68118578-GCC-TCG
• NM_024870.4:c.3355_3357delGCCinsTCG
• PREX2 p.Ala1119Ser

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM5 PP3

The NM_024870.4(PREX2):​c.3355_3357delGCCinsTCG​(p.Ala1119Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1119T) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PREX2 NM_024870.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.69
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr8-68118578-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 545110.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024870.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PREX2	NM_024870.4	MANE Select	c.3355_3357delGCCinsTCG	p.Ala1119Ser	missense	N/A	NP_079146.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PREX2	ENST00000288368.5	TSL:1 MANE Select	c.3355_3357delGCCinsTCG	p.Ala1119Ser	missense	N/A	ENSP00000288368.4	Q70Z35-1
	PREX2	ENST00000854544.1		c.3160_3162delGCCinsTCG	p.Ala1054Ser	missense	N/A	ENSP00000524603.1

Frequencies

GnomAD3 genomes Cov.: 32

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

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.7

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr8-69030813;