Variant rs111487768 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_022835.3(PLEKHG2):c.2308G>A(p.Ala770Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00867 in 1,613,334 control chromosomes in the GnomAD database, including 84 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0063 ( 8 hom., cov: 32)

Exomes 𝑓: 0.0089 ( 76 hom. )

Consequence

PLEKHG2
NM_022835.3 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 1.99

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 Benign. Variant got -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.010281384).

BP6

Variant 19-39423362-G-A is Benign according to our data. Variant chr19-39423362-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 445975.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAd4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
PLEKHG2	NM_022835.3 linkuse as main transcript	c.2308G>A	p.Ala770Thr	missense_variant	18/19	ENST00000425673.6
PLEKHG2	NM_001351693.2 linkuse as main transcript	c.2131G>A	p.Ala711Thr	missense_variant	18/20
PLEKHG2	NM_001351694.2 linkuse as main transcript	c.1677+1074G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLEKHG2	ENST00000425673.6 linkuse as main transcript	c.2308G>A	p.Ala770Thr	missense_variant	18/19	2	NM_022835.3	P2	Q9H7P9-1

Frequencies

GnomAD3 genomes

AF:

0.00632

AC:

962

AN:

152240

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00195

Gnomad AMI

AF:

0.0230

Gnomad AMR

AF:

0.00634

Gnomad ASJ

AF:

0.00692

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00641

Gnomad FIN

AF:

0.00518

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00939

Gnomad OTH

AF:

0.00574

GnomAD3 exomes

AF:

0.00630

AC:

1553

AN:

246502

Hom.:

AF XY:

0.00634

AC XY:

847

AN XY:

133532

show subpopulations

Gnomad AFR exome

AF:

0.00170

Gnomad AMR exome

AF:

0.00406

Gnomad ASJ exome

AF:

0.00691

Gnomad EAS exome

AF:

0.000110

Gnomad SAS exome

AF:

0.00598

Gnomad FIN exome

AF:

0.00493

Gnomad NFE exome

AF:

0.00886

Gnomad OTH exome

AF:

0.00814

GnomAD4 exome

AF:

0.00891

AC:

13021

AN:

1460976

Hom.:

Cov.:

AF XY:

0.00876

AC XY:

6366

AN XY:

726712

show subpopulations

Gnomad4 AFR exome

AF:

0.00203

Gnomad4 AMR exome

AF:

0.00435

Gnomad4 ASJ exome

AF:

0.00701

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.00601

Gnomad4 FIN exome

AF:

0.00474

Gnomad4 NFE exome

AF:

0.0102

Gnomad4 OTH exome

AF:

0.00774

GnomAD4 genome

AF:

0.00631

AC:

961

AN:

152358

Hom.:

Cov.:

AF XY:

0.00609

AC XY:

454

AN XY:

74506

show subpopulations

Gnomad4 AFR

AF:

0.00195

Gnomad4 AMR

AF:

0.00633

Gnomad4 ASJ

AF:

0.00692

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00621

Gnomad4 FIN

AF:

0.00518

Gnomad4 NFE

AF:

0.00939

Gnomad4 OTH

AF:

0.00568

Alfa

AF:

0.00865

Hom.:

Bravo

AF:

0.00613

TwinsUK

AF:

0.00809

AC:

ALSPAC

AF:

0.0101

AC:

ESP6500AA

AF:

0.00340

AC:

ESP6500EA

AF:

0.0108

AC:

ExAC

AF:

0.00605

AC:

734

Asia WGS

AF:

0.00260

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 14, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	PLEKHG2: BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jun 19, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.19

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.018

T;.

Eigen

Uncertain

0.45

Eigen_PC

Uncertain

0.45

FATHMM_MKL

Benign

0.63

LIST_S2

Benign

0.86

D;D

MetaRNN

Benign

0.010

T;T

MetaSVM

Uncertain

0.16

MutationAssessor

Benign

1.5

L;.

MutationTaster

Benign

0.81

D;D;D;D;D

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-1.0

.;N

REVEL

Uncertain

0.38

Sift

Pathogenic

0.0

.;D

Sift4G

Uncertain

0.0050

D;D

Polyphen

1.0

D;D

Vest4

0.39

MVP

0.85

ClinPred

0.028

GERP RS

5.7

Varity_R

0.14

gMVP

0.34

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