rs111487768

Variant names:

• chr19-39423362-G-A
• rs111487768
• NM_022835.3:c.2308G>A

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.99

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]

ACMG classification

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 [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 rank	MANE	Protein	UniProt
PLEKHG2	NM_022835.3	c.2308G>A	p.Ala770Thr	missense_variant	Exon 18 of 19	ENST00000425673.6	NP_073746.2
PLEKHG2	NM_001351693.2	c.2131G>A	p.Ala711Thr	missense_variant	Exon 18 of 20		NP_001338622.1
PLEKHG2	NM_001351694.2	c.1677+1074G>A		intron_variant	Intron 17 of 17		NP_001338623.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLEKHG2	ENST00000425673.6	c.2308G>A	p.Ala770Thr	missense_variant	Exon 18 of 19	2	NM_022835.3	ENSP00000392906.2

Frequencies

GnomAD3 genomes AF: 0.00632 AC: 962 AN: 152240 Hom.: 8 Cov.: 32

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

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.: 76 Cov.: 33 AF XY: 0.00876 AC XY: 6366 AN XY: 726712

Gnomad4 AFR exome AF: 0.00203 AC: 68 AN: 33464

Gnomad4 AMR exome AF: 0.00435 AC: 194 AN: 44560

Gnomad4 ASJ exome AF: 0.00701 AC: 183 AN: 26112

Gnomad4 EAS exome AF: 0.0000756 AC: 3 AN: 39686

Gnomad4 SAS exome AF: 0.00601 AC: 518 AN: 86174

Gnomad4 FIN exome AF: 0.00474 AC: 253 AN: 53356

Gnomad4 NFE exome AF: 0.0102 AC: 11304 AN: 1111518

Gnomad4 Remaining exome AF: 0.00774 AC: 467 AN: 60340

GnomAD4 genome AF: 0.00631 AC: 961 AN: 152358 Hom.: 8 Cov.: 32 AF XY: 0.00609 AC XY: 454 AN XY: 74506

Gnomad4 AFR AF: 0.00195 AC: 0.00194768 AN: 0.00194768

Gnomad4 AMR AF: 0.00633 AC: 0.00633407 AN: 0.00633407

Gnomad4 ASJ AF: 0.00692 AC: 0.00691643 AN: 0.00691643

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00621 AC: 0.00621118 AN: 0.00621118

Gnomad4 FIN AF: 0.00518 AC: 0.00517696 AN: 0.00517696

Gnomad4 NFE AF: 0.00939 AC: 0.00939291 AN: 0.00939291

Gnomad4 OTH AF: 0.00568 AC: 0.00568182 AN: 0.00568182

Alfa AF: 0.00845 Hom.: 18

Bravo AF: 0.00613

TwinsUK AF: 0.00809 AC: 30

ALSPAC AF: 0.0101 AC: 39

ESP6500AA AF: 0.00340 AC: 15

ESP6500EA AF: 0.0108 AC: 93

ExAC AF: 0.00605 AC: 734

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Jan 18, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 19, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PLEKHG2: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.19
CADD	Uncertain	26
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.018	T;.
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Benign	0.63	D
LIST_S2	Benign	0.86	D;D
MetaRNN	Benign	0.010	T;T
MetaSVM	Uncertain	0.16	D
MutationAssessor	Benign	1.5	L;.
PrimateAI	Uncertain	0.49	T
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	T
GERP RS		5.7
Varity_R		0.14
gMVP		0.34
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

dbSNP: rs111487768; hg19: chr19-39914002;