Variant 19-39414124-C-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_022835.3(PLEKHG2):c.38C>G(p.Pro13Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000131 in 152,362 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Consequence

PLEKHG2
NM_022835.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.212

Variant links:

Genes affected

PLEKHG2 (HGNC:29515): (pleckstrin homology and RhoGEF domain containing G2) The protein encoded by this gene is a RhoGTPase that can activate CDC42 by promoting exchange of GDP for GTP on CDC42. The encoded protein is activated by binding to the beta and gamma subunits of heterotrimeric guanine nucleotide-binding protein. Defects in this gene have been associated with leukodystrophy and acquired microcephaly with or without dystonia. [provided by RefSeq, May 2017]

PLEKHG2 links:

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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=0.09426701).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLEKHG2	NM_022835.3 link	c.38C>G	p.Pro13Arg	missense_variant	Exon 2 of 19	ENST00000425673.6	NP_073746.2	Q9H7P9-1
PLEKHG2	NM_001351693.2 link	c.38C>G	p.Pro13Arg	missense_variant	Exon 2 of 20		NP_001338622.1
PLEKHG2	NM_001351694.2 link	c.38C>G	p.Pro13Arg	missense_variant	Exon 2 of 18		NP_001338623.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLEKHG2	ENST00000425673.6 link	c.38C>G	p.Pro13Arg	missense_variant	Exon 2 of 19	2	NM_022835.3	ENSP00000392906.2		Q9H7P9-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152244

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152362

Hom.:

Cov.:

AF XY:

0.0000268

AC XY:

AN XY:

74510

show subpopulations

Gnomad4 AFR

AF:

0.0000481

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000282

Hom.:

Bravo

AF:

0.0000227

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jul 28, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.38C>G (p.P13R) alteration is located in exon 2 (coding exon 1) of the PLEKHG2 gene. This alteration results from a C to G substitution at nucleotide position 38, causing the proline (P) at amino acid position 13 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.058

BayesDel_noAF

Benign

-0.32

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.0033

T;.;.;.;.;.

Eigen

Benign

-0.21

Eigen_PC

Benign

-0.23

FATHMM_MKL

Benign

0.46

LIST_S2

Benign

0.72

T;T;T;T;T;T

M_CAP

Uncertain

0.16

MetaRNN

Benign

0.094

T;T;T;T;T;T

MetaSVM

Benign

-0.70

MutationAssessor

Benign

1.2

L;.;.;.;L;.

PrimateAI

Benign

0.47

PROVEAN

Benign

-0.50

N;.;N;N;N;N

REVEL

Benign

0.11

Sift

Pathogenic

0.0

D;.;D;D;D;D

Sift4G

Uncertain

0.0050

D;D;D;D;D;D

Polyphen

1.0

D;.;B;.;D;.

Vest4

0.12

MutPred

0.21

Loss of ubiquitination at K12 (P = 0.013);Loss of ubiquitination at K12 (P = 0.013);Loss of ubiquitination at K12 (P = 0.013);Loss of ubiquitination at K12 (P = 0.013);Loss of ubiquitination at K12 (P = 0.013);Loss of ubiquitination at K12 (P = 0.013);

MVP

0.73

ClinPred

0.27

GERP RS

1.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.071

gMVP

0.49

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over