Genetic Variant NM_022835.3:c.155C>A (chr19-39415037-C-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_022835.3(PLEKHG2):c.155C>A(p.Ser52Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S52F) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

PLEKHG2
NM_022835.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.588

Publications

2 publications found

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 Gene-Disease associations (from GenCC):

leukodystrophy and acquired microcephaly with or without dystonia;
Inheritance: AR Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Illumina, Labcorp Genetics (formerly Invitae)
epilepsy
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

PLEKHG2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.30499893).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022835.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PLEKHG2	NM_022835.3	MANE Select	c.155C>A	p.Ser52Tyr	missense	Exon 3 of 19	NP_073746.2	Q9H7P9-1
PLEKHG2	NM_001351694.2		c.155C>A	p.Ser52Tyr	missense	Exon 3 of 18	NP_001338623.1	Q9H7P9-2
PLEKHG2	NM_001351693.2		c.110-132C>A		intron	N/A	NP_001338622.1	E7ESZ3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PLEKHG2	ENST00000425673.6	TSL:2 MANE Select	c.155C>A	p.Ser52Tyr	missense	Exon 3 of 19	ENSP00000392906.2	Q9H7P9-1
PLEKHG2	ENST00000942561.1		c.155C>A	p.Ser52Tyr	missense	Exon 2 of 18	ENSP00000612620.1
PLEKHG2	ENST00000942562.1		c.155C>A	p.Ser52Tyr	missense	Exon 3 of 19	ENSP00000612621.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1447096

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

718490

African (AFR)

AF:

0.00

AC:

AN:

32992

American (AMR)

AF:

0.00

AC:

AN:

43448

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25840

East Asian (EAS)

AF:

0.00

AC:

AN:

38798

South Asian (SAS)

AF:

0.00

AC:

AN:

84020

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51726

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5750

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1104776

Other (OTH)

AF:

0.00

AC:

AN:

59746

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.55

BayesDel_addAF

Benign

-0.032

BayesDel_noAF

Benign

-0.28

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.093

Eigen

Uncertain

0.21

Eigen_PC

Benign

0.16

FATHMM_MKL

Benign

0.54

LIST_S2

Benign

0.86

M_CAP

Uncertain

0.17

MetaRNN

Benign

0.30

MetaSVM

Uncertain

-0.24

MutationAssessor

Uncertain

2.0

PhyloP100

0.59

PrimateAI

Pathogenic

0.84

PROVEAN

Uncertain

-2.6

REVEL

Benign

0.18

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0010

Polyphen

0.99

Vest4

0.30

MutPred

0.29

Loss of glycosylation at S52 (P = 0.017)

MVP

0.75

ClinPred

0.99

GERP RS

4.5

PromoterAI

-0.0034

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.60

gMVP

0.49

Mutation Taster

=71/29

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over