Variant 12-6313740-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001384598.1(PLEKHG6):c.250G>A(p.Gly84Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000139 in 1,608,802 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000092 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00014 ( 0 hom. )

Consequence

PLEKHG6
NM_001384598.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.30

Variant links:

Genes affected

PLEKHG6 (HGNC:25562): (pleckstrin homology and RhoGEF domain containing G6) Predicted to enable guanyl-nucleotide exchange factor activity. Predicted to be involved in regulation of small GTPase mediated signal transduction. Located in cell junction and centrosome. [provided by Alliance of Genome Resources, Apr 2022]

PLEKHG6 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLEKHG6	NM_001384598.1 linkuse as main transcript	c.250G>A	p.Gly84Arg	missense_variant	3/16	ENST00000684764.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLEKHG6	ENST00000684764.1 linkuse as main transcript	c.250G>A	p.Gly84Arg	missense_variant	3/16		NM_001384598.1	P1	Q3KR16-1

Frequencies

GnomAD3 genomes

AF:

0.0000920

AC:

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.000956

GnomAD3 exomes

AF:

0.000123

AC:

AN:

244636

Hom.:

AF XY:

0.000128

AC XY:

AN XY:

132672

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000150

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000268

Gnomad FIN exome

AF:

0.000281

Gnomad NFE exome

AF:

0.0000814

Gnomad OTH exome

AF:

0.000338

GnomAD4 exome

AF:

0.000143

AC:

209

AN:

1456474

Hom.:

Cov.:

AF XY:

0.000146

AC XY:

106

AN XY:

724448

show subpopulations

Gnomad4 AFR exome

AF:

0.0000602

Gnomad4 AMR exome

AF:

0.000115

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000151

Gnomad4 SAS exome

AF:

0.000152

Gnomad4 FIN exome

AF:

0.000207

Gnomad4 NFE exome

AF:

0.000152

Gnomad4 OTH exome

AF:

0.0000332

GnomAD4 genome

AF:

0.0000919

AC:

AN:

152328

Hom.:

Cov.:

AF XY:

0.0000940

AC XY:

AN XY:

74480

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.000118

Gnomad4 OTH

AF:

0.000946

Alfa

AF:

0.000113

Hom.:

Bravo

AF:

0.0000869

ExAC

AF:

0.0000988

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 02, 2022

The c.250G>A (p.G84R) alteration is located in exon 3 (coding exon 2) of the PLEKHG6 gene. This alteration results from a G to A substitution at nucleotide position 250, causing the glycine (G) at amino acid position 84 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.048

BayesDel_noAF

Uncertain

-0.010

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.032

T;.;T;.

Eigen

Uncertain

0.41

Eigen_PC

Uncertain

0.30

FATHMM_MKL

Benign

0.73

M_CAP

Benign

0.043

MetaRNN

Uncertain

0.54

D;D;D;D

MetaSVM

Uncertain

-0.091

MutationAssessor

Uncertain

2.8

M;.;M;.

MutationTaster

Benign

0.52

N;N;N;N

PrimateAI

Benign

0.43

PROVEAN

Benign

-2.2

N;D;N;D

REVEL

Uncertain

0.37

Sift

Uncertain

0.0010

D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D

Polyphen

1.0

D;D;D;D

Vest4

0.56

MutPred

0.38

Gain of catalytic residue at K81 (P = 5e-04);Gain of catalytic residue at K81 (P = 5e-04);Gain of catalytic residue at K81 (P = 5e-04);.;

MVP

0.66

MPC

0.34

ClinPred

0.35

GERP RS

4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.18

gMVP

0.40

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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