NM_022835.3:c.137C>G

Variant names:

• chr19-39415019-C-G
• NM_022835.3:c.137C>G

Variant summary

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

The NM_022835.3(PLEKHG2):​c.137C>G​(p.Pro46Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000277 in 1,445,836 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: 0.0000028 (0 hom.)
• Consequence: PLEKHG2 NM_022835.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.57

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=0.19177493).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLEKHG2	NM_022835.3	c.137C>G	p.Pro46Arg	missense_variant	Exon 3 of 19	ENST00000425673.6	NP_073746.2
PLEKHG2	NM_001351694.2	c.137C>G	p.Pro46Arg	missense_variant	Exon 3 of 18		NP_001338623.1
PLEKHG2	NM_001351693.2	c.110-150C>G		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.137C>G	p.Pro46Arg	missense_variant	Exon 3 of 19	2	NM_022835.3	ENSP00000392906.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000277 AC: 4 AN: 1445836 Hom.: 0 Cov.: 31 AF XY: 0.00000279 AC XY: 2 AN XY: 717182

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000257

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000272

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.043	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0060	T;.;.;.
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.21
FATHMM_MKL	Benign	0.52	D
LIST_S2	Benign	0.80	T;T;T;T
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.19	T;T;T;T
MetaSVM	Benign	-0.68	T
MutationAssessor	Benign	1.7	L;.;L;.
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-2.1	N;D;N;D
REVEL	Benign	0.14
Sift	Uncertain	0.0010	D;D;D;T
Sift4G	Uncertain	0.0040	D;D;D;D
Polyphen		0.91	P;.;P;.
Vest4		0.30
MutPred		0.29		Gain of MoRF binding (P = 0.0065);.;Gain of MoRF binding (P = 0.0065);.;
MVP		0.68
ClinPred		0.95	D
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.11
gMVP		0.33

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-39905659;