19-39415019-C-T

Variant names:

• chr19-39415019-C-T
• rs1211640713
• NM_022835.3:c.137C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_022835.3(PLEKHG2):​c.137C>T​(p.Pro46Leu) 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. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. P46P) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PLEKHG2 NM_022835.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.57
• Publications: 0 publications found

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]

PLEKHG2 Gene-Disease associations (from GenCC):

• leukodystrophy and acquired microcephaly with or without dystonia;

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Illumina, Labcorp Genetics (formerly Invitae)
• epilepsy

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06992182).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022835.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLEKHG2	NM_022835.3	MANE Select	c.137C>T	p.Pro46Leu	missense	Exon 3 of 19	NP_073746.2	Q9H7P9-1
	PLEKHG2	NM_001351694.2		c.137C>T	p.Pro46Leu	missense	Exon 3 of 18	NP_001338623.1	Q9H7P9-2
	PLEKHG2	NM_001351693.2		c.110-150C>T		intron	N/A	NP_001338622.1	E7ESZ3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLEKHG2	ENST00000425673.6	TSL:2 MANE Select	c.137C>T	p.Pro46Leu	missense	Exon 3 of 19	ENSP00000392906.2	Q9H7P9-1
	PLEKHG2	ENST00000942561.1		c.137C>T	p.Pro46Leu	missense	Exon 2 of 18	ENSP00000612620.1
	PLEKHG2	ENST00000942562.1		c.137C>T	p.Pro46Leu	missense	Exon 3 of 19	ENSP00000612621.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000221 AC: 5 AN: 226090 AF XY: 0.0000162

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000151

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000484 AC: 7 AN: 1445836 Hom.: 0 Cov.: 31 AF XY: 0.00000418 AC XY: 3 AN XY: 717182

African (AFR) AF: 0.00 AC: 0 AN: 33000

American (AMR) AF: 0.000160 AC: 7 AN: 43624

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25780

East Asian (EAS) AF: 0.00 AC: 0 AN: 38986

South Asian (SAS) AF: 0.00 AC: 0 AN: 84420

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51782

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5742

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1102868

Other (OTH) AF: 0.00 AC: 0 AN: 59634

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	14
DANN	Benign	0.84
DEOGEN2	Benign	0.0055	T
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.53
FATHMM_MKL	Benign	0.43	N
LIST_S2	Benign	0.78	T
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.070	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.64	N
PhyloP100		2.6
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-2.8	D
REVEL	Benign	0.069
Sift	Benign	0.049	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.0050	B
Vest4		0.21
MutPred		0.28		Loss of relative solvent accessibility (P = 0.0186)
MVP		0.35
ClinPred		0.20	T
GERP RS		3.9
PromoterAI		0.013	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.073
gMVP		0.29
Mutation Taster		=91/9	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

Other links and lift over

dbSNP: rs1211640713; hg19: chr19-39905659;