19-39415022-G-C

Variant names:

• chr19-39415022-G-C
• rs114725664
• NM_022835.3:c.140G>C

Variant summary

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

The NM_022835.3(PLEKHG2):​c.140G>C​(p.Arg47Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,444,418 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PLEKHG2 NM_022835.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.143

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLEKHG2	NM_022835.3	c.140G>C	p.Arg47Pro	missense_variant	Exon 3 of 19	ENST00000425673.6	NP_073746.2
PLEKHG2	NM_001351694.2	c.140G>C	p.Arg47Pro	missense_variant	Exon 3 of 18		NP_001338623.1
PLEKHG2	NM_001351693.2	c.110-147G>C		intron_variant	Intron 2 of 19		NP_001338622.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLEKHG2	ENST00000425673.6	c.140G>C	p.Arg47Pro	missense_variant	Exon 3 of 19	2	NM_022835.3	ENSP00000392906.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000448 AC: 1 AN: 222978 Hom.: 0 AF XY: 0.00000820 AC XY: 1 AN XY: 122020

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000103

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1444418 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 716264

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000181

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ExAC AF: 0.00000826 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Uncertain	0.022	T
BayesDel_noAF	Benign	-0.21
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Benign	0.015	T;.;.;.
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.86	D;T;D;T
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.36	T;T;T;T
MetaSVM	Uncertain	-0.072	T
MutationAssessor	Uncertain	2.0	M;.;M;.
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-1.7	N;N;N;N
REVEL	Benign	0.23
Sift	Uncertain	0.0010	D;D;D;D
Sift4G	Uncertain	0.016	D;D;T;D
Polyphen		1.0	D;.;D;.
Vest4		0.36
MutPred		0.32		Loss of solvent accessibility (P = 8e-04);.;Loss of solvent accessibility (P = 8e-04);.;
MVP		0.82
ClinPred		0.88	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.29
gMVP		0.40

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.40		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.40		Position offset: 3

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

Publications

LitVar

Other links and lift over

dbSNP: rs114725664; hg19: chr19-39905662;