rs111487768

Variant names:

Variant summary

Our verdict is Benign. The variant received -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

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

Conservation

PhyloP100: 1.99

Publications

5 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: Labcorp Genetics (formerly Invitae), Illumina, Ambry Genetics
epilepsy
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

PLEKHG2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 445975.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAd4 at 8 AD,AR gene

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
PLEKHG2	NM_022835.3	MANE Select	c.2308G>A	p.Ala770Thr	missense	Exon 18 of 19	NP_073746.2
PLEKHG2	NM_001351693.2		c.2131G>A	p.Ala711Thr	missense	Exon 18 of 20	NP_001338622.1
PLEKHG2	NM_001351694.2		c.1677+1074G>A		intron	N/A	NP_001338623.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PLEKHG2	ENST00000425673.6	TSL:2 MANE Select	c.2308G>A	p.Ala770Thr	missense	Exon 18 of 19	ENSP00000392906.2
PLEKHG2	ENST00000205135.8	TSL:1	c.1909G>A	p.Ala637Thr	missense	Exon 14 of 15	ENSP00000205135.3
PLEKHG2	ENST00000458508.6	TSL:2	c.2131G>A	p.Ala711Thr	missense	Exon 18 of 20	ENSP00000408857.2

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

GnomAD2 exomes

AF:

0.00630

AC:

1553

AN:

246502

AF XY:

0.00634

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 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

African (AFR)

AF:

0.00203

AC:

AN:

33464

American (AMR)

AF:

0.00435

AC:

194

AN:

44560

Ashkenazi Jewish (ASJ)

AF:

0.00701

AC:

183

AN:

26112

East Asian (EAS)

AF:

0.0000756

AC:

AN:

39686

South Asian (SAS)

AF:

0.00601

AC:

518

AN:

86174

European-Finnish (FIN)

AF:

0.00474

AC:

253

AN:

53356

Middle Eastern (MID)

AF:

0.00538

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0102

AC:

11304

AN:

1111518

Other (OTH)

AF:

0.00774

AC:

467

AN:

60340

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

909

1817

2726

3634

4543

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

436

872

1308

1744

2180

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00631

AC:

961

AN:

152358

Hom.:

Cov.:

AF XY:

0.00609

AC XY:

454

AN XY:

74506

show subpopulations

African (AFR)

AF:

0.00195

AC:

AN:

41588

American (AMR)

AF:

0.00633

AC:

AN:

15314

Ashkenazi Jewish (ASJ)

AF:

0.00692

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00621

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00518

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00939

AC:

639

AN:

68030

Other (OTH)

AF:

0.00568

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

108

163

217

271

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00845

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

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.19

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.018

Eigen

Uncertain

0.45

Eigen_PC

Uncertain

0.45

FATHMM_MKL

Benign

0.63

LIST_S2

Benign

0.86

MetaRNN

Benign

0.010

MetaSVM

Uncertain

0.16

MutationAssessor

Benign

1.5

PhyloP100

2.0

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-1.0

REVEL

Uncertain

0.38

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0050

Polyphen

1.0

Vest4

0.39

MVP

0.85

ClinPred

0.028

GERP RS

5.7

PromoterAI

-0.18

Neutral

(source)

Varity_R

0.14

gMVP

0.34

Mutation Taster

=98/2

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

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over