19-39416866-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PP5BP4

The NM_022835.3(PLEKHG2):c.610C>T(p.Arg204Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000223 in 1,608,326 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00038 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00021 ( 2 hom. )

Consequence

PLEKHG2
NM_022835.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:7U:1

Conservation

PhyloP100: 3.45

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PP5

Variant 19-39416866-C-T is Pathogenic according to our data. Variant chr19-39416866-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 522394.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=5, Uncertain_significance=1, Pathogenic=1}.

BP4

Computational evidence support a benign effect (MetaRNN=0.35702795). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLEKHG2	NM_022835.3 link	c.610C>T	p.Arg204Trp	missense_variant	Exon 7 of 19	ENST00000425673.6	NP_073746.2	Q9H7P9-1
PLEKHG2	NM_001351693.2 link	c.433C>T	p.Arg145Trp	missense_variant	Exon 7 of 20		NP_001338622.1
PLEKHG2	NM_001351694.2 link	c.610C>T	p.Arg204Trp	missense_variant	Exon 7 of 18		NP_001338623.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PLEKHG2	ENST00000425673.6 link	c.610C>T	p.Arg204Trp	missense_variant	Exon 7 of 19	2	NM_022835.3	ENSP00000392906.2	Q9H7P9-1
PLEKHG2	ENST00000205135.8 link	c.298C>T	p.Arg100Trp	missense_variant	Exon 5 of 15	1		ENSP00000205135.3	H7BXC7
PLEKHG2	ENST00000458508.6 link	c.433C>T	p.Arg145Trp	missense_variant	Exon 7 of 20	2		ENSP00000408857.2	E7ESZ3
PLEKHG2	ENST00000409797.6 link	c.610C>T	p.Arg204Trp	missense_variant	Exon 7 of 18	2		ENSP00000386492.1	Q9H7P9-2

Frequencies

GnomAD3 genomes

AF:

0.000381

AC:

AN:

152212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000785

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00115

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00207

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000191

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000356

AC:

AN:

241264

Hom.:

AF XY:

0.000326

AC XY:

AN XY:

131864

show subpopulations

Gnomad AFR exome

AF:

0.0000668

Gnomad AMR exome

AF:

0.000178

Gnomad ASJ exome

AF:

0.000724

Gnomad EAS exome

AF:

0.00140

Gnomad SAS exome

AF:

0.0000999

Gnomad FIN exome

AF:

0.00160

Gnomad NFE exome

AF:

0.0000921

Gnomad OTH exome

AF:

0.000170

GnomAD4 exome

AF:

0.000206

AC:

300

AN:

1455996

Hom.:

Cov.:

AF XY:

0.000206

AC XY:

149

AN XY:

724234

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000137

Gnomad4 ASJ exome

AF:

0.000736

Gnomad4 EAS exome

AF:

0.00224

Gnomad4 SAS exome

AF:

0.0000817

Gnomad4 FIN exome

AF:

0.00142

Gnomad4 NFE exome

AF:

0.0000676

Gnomad4 OTH exome

AF:

0.000482

GnomAD4 genome

AF:

0.000381

AC:

AN:

152330

Hom.:

Cov.:

AF XY:

0.000550

AC XY:

AN XY:

74486

show subpopulations

Gnomad4 AFR

AF:

0.0000481

Gnomad4 AMR

AF:

0.000784

Gnomad4 ASJ

AF:

0.000576

Gnomad4 EAS

AF:

0.00116

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00207

Gnomad4 NFE

AF:

0.000191

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000194

Hom.:

Bravo

AF:

0.000200

ESP6500AA

AF:

0.000229

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000190

AC:

Asia WGS

AF:

0.00260

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:7Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Leukodystrophy and acquired microcephaly with or without dystonia;

Pathogenic:5

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2_Supporting+PM3+PP1+PP4+PS3_Moderate -

Aug 12, 2020

Genetics and Molecular Pathology, SA Pathology

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The PLEKHG2 c.610C>T missense variant is classified as Likely Pathogenic (PP1_moderate, PS3_moderate, PS4_moderate) The PLEKHG2 c.610C>T missense variant is a single nucleotide change in exon 7 of the PLEKHG2 gene, which is predicted to change the amino acid arginine at position 204 in the protein to tryptophan. This variant has been reported in a homozygous state in five patients with profound mental retardation, dystonia, postnatal microcephaly, and common brain MRI findings, from two unrelated consanguinous families (PS4_moderate). This variant cosegregated with disease and heterozyous carriers of this variant were unaffected (PMID:26573021) (PP1_moderate). Functional studies demonstrate decreased basal and stimulated RhoGEF activity of the R204 mutant compared with wildtype in luciferase assays, suggesting the R204 variant impairs the ability of the PLEKHG2 catalytic domain to form an active conformation (PMID:26573021) (PS3_moderate). This variant has been reported in dbSNP (rs20101843) and has been reported in population databases (gnomAD = 0.035%, 96 of 272616 sequenced alleles, no homozygotes). This variant has been reported in ClinVar as pathogenic for Leukodystrophy and aquired microcephaly with or without dystonia (Variation ID: VCV000522394.1). It has also been reported as damaging in HGMD for mental retardation, dystonia and postnatal microcephaly (CM1617668). Computational predictions are equivocal. -

Aug 31, 2023

Intergen, Intergen Genetics and Rare Diseases Diagnosis Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 27, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: PLEKHG2 c.610C>T (p.Arg204Trp) results in a non-conservative amino acid change located in the Dbl homology (DH) domain (IPR000219) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00036 in 241264 control chromosomes (gnomAD). c.610C>T has been reported in the literature in two unrelated consanguineous families (in homozygous state) affected with Microcephaly-dystonia (example: Edvardson_2016). These data indicate that the variant is likely to be associated with disease. Experimental evidence evaluating an impact on protein function suggests this variant can impair normal protein function (example: Edvardson_2016). The following publication has been ascertained in the context of this evaluation (PMID: 26573021). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Sep 30, 2024

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided

Pathogenic:1Uncertain:1

Nov 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 204 of the PLEKHG2 protein (p.Arg204Trp). This variant is present in population databases (rs201201843, gnomAD 0.1%). This missense change has been observed in individuals with acquired microcephaly with or without dystonia (PMID: 26573021). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 522394). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects PLEKHG2 function (PMID: 26573021). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Sep 30, 2022

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies suggest R204W impairs catalytic activity and causes defects in dendritic spine morphology formation (Edvardson et al., 2016; Nishikawa et al., 2022); Reported in multiple individuals from two unrelated families with severe developmental delay, postnatal microcephaly, hypotonia, leukodystrophy, variable presence of dystonia, and seizures (Edvardson et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Variants in candidate genes are classified as variants of uncertain significance in accordance with ACMG guidelines (Richards et al., 2015); This variant is associated with the following publications: (PMID: 34426522, 35203342, 26573021) -

PLEKHG2-related disorder

Pathogenic:1

Apr 20, 2023

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The PLEKHG2 c.610C>T variant is predicted to result in the amino acid substitution p.Arg204Trp. This variant has been reported in the homozygous state in multiple individuals among two families with profound intellectual disability, dystonia, postnatal microcephaly, and distinct neuroimaging profiles (Edvardson et al. 2016. PubMed ID: 26573021). This variant is reported in 0.15% of alleles in individuals of European (Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/19-39907506-C-T). This variant is interpreted as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.43

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.11

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.16

T;.;.

Eigen

Uncertain

0.62

Eigen_PC

Uncertain

0.55

FATHMM_MKL

Benign

0.49

LIST_S2

Uncertain

0.94

D;D;D

M_CAP

Uncertain

0.17

MetaRNN

Benign

0.36

T;T;T

MetaSVM

Uncertain

0.064

MutationAssessor

Uncertain

2.8

M;.;M

PrimateAI

Uncertain

0.73

PROVEAN

Uncertain

-3.1

D;D;D

REVEL

Uncertain

0.34

Sift

Pathogenic

0.0

D;D;D

Sift4G

Uncertain

0.0060

D;D;D

Polyphen

1.0

D;D;D

Vest4

0.70

MVP

0.82

ClinPred

0.094

GERP RS

4.9

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.6

Varity_R

0.82

gMVP

0.66

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.10

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