19-39414994-C-G

Variant names:

• chr19-39414994-C-G
• rs767924564
• NM_022835.3:c.112C>G

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.112C>G​(p.Pro38Ala) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000694 in 1,440,666 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P38S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: PLEKHG2 NM_022835.3 missense, splice_region
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.44
• 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=0.08638948).

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.112C>G	p.Pro38Ala	missense splice_region	Exon 3 of 19	NP_073746.2	Q9H7P9-1
	PLEKHG2	NM_001351694.2		c.112C>G	p.Pro38Ala	missense splice_region	Exon 3 of 18	NP_001338623.1	Q9H7P9-2
	PLEKHG2	NM_001351693.2		c.110-175C>G		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.112C>G	p.Pro38Ala	missense splice_region	Exon 3 of 19	ENSP00000392906.2	Q9H7P9-1
	PLEKHG2	ENST00000451354.6	TSL:5	c.115C>G	p.Pro39Ala	missense	Exon 2 of 5	ENSP00000412818.1	C9JVL3
	PLEKHG2	ENST00000438123.5	TSL:3	c.115C>G	p.Pro39Ala	missense	Exon 3 of 3	ENSP00000397615.1	C9J7S4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000445 AC: 1 AN: 224540 AF XY: 0.00

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000101

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.94e-7 AC: 1 AN: 1440666 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 713966

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32864

American (AMR) AF: 0.00 AC: 0 AN: 43036

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25326

East Asian (EAS) AF: 0.00 AC: 0 AN: 38980

South Asian (SAS) AF: 0.00 AC: 0 AN: 84068

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51588

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5696

European-Non Finnish (NFE) AF: 9.09e-7 AC: 1 AN: 1099714

Other (OTH) AF: 0.00 AC: 0 AN: 59394

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000829 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.056
BayesDel_addAF	Benign	-0.088	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	15
DANN	Benign	0.86
DEOGEN2	Benign	0.0050	T
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.65
FATHMM_MKL	Benign	0.36	N
LIST_S2	Benign	0.50	T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.083	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.8	L
PhyloP100		1.4
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.032
Sift	Benign	0.052	T
Sift4G	Benign	0.087	T
Polyphen		0.15	B
Vest4		0.31
MutPred		0.27		Loss of glycosylation at P38 (P = 0.0211)
MVP		0.46
ClinPred		0.041	T
GERP RS		1.5
PromoterAI		0.016	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.048
gMVP		0.29
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs767924564; hg19: chr19-39905634;