Variant 19-39415022-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_022835.3(PLEKHG2):c.140G>A(p.Arg47Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00101 in 1,596,634 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0050 ( 9 hom., cov: 32)

Exomes 𝑓: 0.00059 ( 8 hom. )

Consequence

PLEKHG2
NM_022835.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.143

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 Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0052300096).

BP6

Variant 19-39415022-G-A is Benign according to our data. Variant chr19-39415022-G-A is described in ClinVar as [Benign]. Clinvar id is 711220.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.005 (761/152220) while in subpopulation AFR AF= 0.0176 (731/41526). AF 95% confidence interval is 0.0165. There are 9 homozygotes in gnomad4. There are 373 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PLEKHG2	NM_022835.3 linkuse as main transcript	c.140G>A	p.Arg47Gln	missense_variant	3/19	ENST00000425673.6	NP_073746.2	Q9H7P9-1
PLEKHG2	NM_001351694.2 linkuse as main transcript	c.140G>A	p.Arg47Gln	missense_variant	3/18		NP_001338623.1
PLEKHG2	NM_001351693.2 linkuse as main transcript	c.110-147G>A		intron_variant			NP_001338622.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PLEKHG2	ENST00000425673.6 linkuse as main transcript	c.140G>A	p.Arg47Gln	missense_variant	3/19	2	NM_022835.3	ENSP00000392906.2		Q9H7P9-1

Frequencies

GnomAD3 genomes

AF:

0.00497

AC:

756

AN:

152104

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0175

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00144

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:

0.00431

GnomAD3 exomes

AF:

0.00133

AC:

297

AN:

222978

Hom.:

AF XY:

0.00105

AC XY:

128

AN XY:

122020

show subpopulations

Gnomad AFR exome

AF:

0.0196

Gnomad AMR exome

AF:

0.000881

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000356

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000308

Gnomad OTH exome

AF:

0.00144

GnomAD4 exome

AF:

0.000593

AC:

856

AN:

1444414

Hom.:

Cov.:

AF XY:

0.000517

AC XY:

370

AN XY:

716262

show subpopulations

Gnomad4 AFR exome

AF:

0.0220

Gnomad4 AMR exome

AF:

0.000851

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000475

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000136

Gnomad4 OTH exome

AF:

0.00116

GnomAD4 genome

AF:

0.00500

AC:

761

AN:

152220

Hom.:

Cov.:

AF XY:

0.00501

AC XY:

373

AN XY:

74420

show subpopulations

Gnomad4 AFR

AF:

0.0176

Gnomad4 AMR

AF:

0.00137

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:

0.00426

Alfa

AF:

0.000718

Hom.:

Bravo

AF:

0.00571

ESP6500AA

AF:

0.0106

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00152

AC:

184

Asia WGS

AF:

0.00144

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 08, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.35

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.0044

T;.;.;.

Eigen

Uncertain

0.29

Eigen_PC

Uncertain

0.30

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.91

D;D;D;D

MetaRNN

Benign

0.0052

T;T;T;T

MetaSVM

Benign

-0.61

MutationAssessor

Uncertain

2.0

M;.;M;.

MutationTaster

Benign

0.63

D;D;D;D;D

PrimateAI

Uncertain

0.75

PROVEAN

Benign

-1.0

N;N;N;N

REVEL

Benign

0.14

Sift

Uncertain

0.019

D;D;T;D

Sift4G

Uncertain

0.027

D;D;T;D

Polyphen

1.0

D;.;D;.

Vest4

0.26

MVP

0.72

ClinPred

0.028

GERP RS

5.0

Varity_R

0.14

gMVP

0.24

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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