19-39414189-C-T

Position:

• chr19-39414189-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_022835.3(PLEKHG2):​c.103C>T​(p.Arg35Trp) 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PLEKHG2 NM_022835.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.313

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

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2020311).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PLEKHG2	NM_022835.3	c.103C>T	p.Arg35Trp	missense_variant	2/19	ENST00000425673.6	NP_073746.2
PLEKHG2	NM_001351693.2	c.103C>T	p.Arg35Trp	missense_variant	2/20		NP_001338622.1
PLEKHG2	NM_001351694.2	c.103C>T	p.Arg35Trp	missense_variant	2/18		NP_001338623.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PLEKHG2	ENST00000425673.6	c.103C>T	p.Arg35Trp	missense_variant	2/19	2	NM_022835.3	ENSP00000392906.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 03, 2022

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 35 of the PLEKHG2 protein (p.Arg35Trp). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with PLEKHG2-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.069	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0040	T;.;.;.;.;.
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.43
FATHMM_MKL	Benign	0.083	N
LIST_S2	Uncertain	0.92	D;T;D;D;D;D
M_CAP	Uncertain	0.24	D
MetaRNN	Benign	0.20	T;T;T;T;T;T
MetaSVM	Benign	-0.74	T
MutationAssessor	Benign	1.0	L;.;.;.;L;.
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Uncertain	0.48	T
PROVEAN	Uncertain	-2.5	N;.;N;N;N;N
REVEL	Benign	0.16
Sift	Uncertain	0.0040	D;.;D;D;D;D
Sift4G	Uncertain	0.017	D;D;D;D;D;D
Polyphen		0.99	D;.;D;.;D;.
Vest4		0.19
MutPred		0.26		Gain of catalytic residue at P38 (P = 0.0334);Gain of catalytic residue at P38 (P = 0.0334);Gain of catalytic residue at P38 (P = 0.0334);Gain of catalytic residue at P38 (P = 0.0334);Gain of catalytic residue at P38 (P = 0.0334);Gain of catalytic residue at P38 (P = 0.0334);
MVP		0.62
ClinPred		0.76	D
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.085
gMVP		0.32

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-39904829;