Variant 19-39415048-A-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.166A>G(p.Ser56Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000208 in 1,445,544 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 (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

PLEKHG2
NM_022835.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.38

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=0.1920073).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLEKHG2	NM_022835.3 link	c.166A>G	p.Ser56Gly	missense_variant	Exon 3 of 19	ENST00000425673.6	NP_073746.2	Q9H7P9-1
PLEKHG2	NM_001351694.2 link	c.166A>G	p.Ser56Gly	missense_variant	Exon 3 of 18		NP_001338623.1
PLEKHG2	NM_001351693.2 link	c.110-121A>G		intron_variant	Intron 2 of 19		NP_001338622.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLEKHG2	ENST00000425673.6 link	c.166A>G	p.Ser56Gly	missense_variant	Exon 3 of 19	2	NM_022835.3	ENSP00000392906.2		Q9H7P9-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000208

AC:

AN:

1445544

Hom.:

Cov.:

AF XY:

0.00000279

AC XY:

AN XY:

717834

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000181

Gnomad4 OTH exome

AF:

0.0000167

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 06, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.166A>G (p.S56G) alteration is located in exon 3 (coding exon 2) of the PLEKHG2 gene. This alteration results from a A to G substitution at nucleotide position 166, causing the serine (S) at amino acid position 56 to be replaced by a glycine (G). 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

Uncertain

0.42

BayesDel_addAF

Benign

-0.019

BayesDel_noAF

Benign

-0.27

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.023

T;.;.;.

Eigen

Benign

0.068

Eigen_PC

Benign

0.045

FATHMM_MKL

Benign

0.27

LIST_S2

Benign

0.81

T;T;T;T

M_CAP

Benign

0.077

MetaRNN

Benign

0.19

T;T;T;T

MetaSVM

Benign

-0.42

MutationAssessor

Uncertain

2.0

M;.;M;.

PrimateAI

Pathogenic

0.82

PROVEAN

Benign

-0.57

N;N;N;N

REVEL

Benign

0.13

Sift

Pathogenic

0.0

D;D;D;T

Sift4G

Benign

0.067

T;D;T;D

Polyphen

0.96

P;.;D;.

Vest4

0.47

MutPred

0.18

Loss of phosphorylation at S56 (P = 0.0072);.;Loss of phosphorylation at S56 (P = 0.0072);.;

MVP

0.79

ClinPred

0.96

GERP RS

5.0

Varity_R

0.26

gMVP

0.40

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over