PLEKHG2

pleckstrin homology and RhoGEF domain containing G2, the group of Pleckstrin homology domain containing|Dbl family Rho GEFs

Basic information

Region (hg38): 19:39412668-39428415

Links

ENSG00000090924 ∙ NCBI:64857 ∙ OMIM:611893 ∙ HGNC:29515 ∙ Uniprot:Q9H7P9 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• leukodystrophy and acquired microcephaly with or without dystonia; (Limited), mode of inheritance: AR
• leukodystrophy and acquired microcephaly with or without dystonia; (Strong), mode of inheritance: AR
• leukodystrophy and acquired microcephaly with or without dystonia; (Limited), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Leukodystrophy and acquired microcephaly with or without dystonia	AR	General	Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing	Neurologic	26573021

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the PLEKHG2 gene.

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the PLEKHG2 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			2	103	11	116
missense		1	217	17	15	250
nonsense		1	4			5
start loss						0
frameshift			6			6
inframe indel						0
splice donor/acceptor (+/-2bp)						0
splice region			8	8	2	18
non coding			1	33	8	42
Total	0	2	230	153	34

Variants in PLEKHG2

This is a list of pathogenic ClinVar variants found in the PLEKHG2 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
19-39414101-C-T			Likely benign (Apr 11, 2023)
19-39414106-G-A			Uncertain significance (May 21, 2022)
19-39414128-C-G			Likely benign (Mar 18, 2023)
19-39414137-C-T			Likely benign (Jan 20, 2023)
19-39414144-G-T		not specified	Uncertain significance (Mar 16, 2022)
19-39414189-C-T			Uncertain significance (Aug 03, 2022)
19-39414206-A-C			Likely benign (Oct 05, 2022)
19-39414985-C-T			Likely benign (Aug 08, 2018)
19-39414994-C-T		Leukodystrophy and acquired microcephaly with or without dystonia;	Uncertain significance (Apr 03, 2018)
19-39414996-T-C			Likely benign (Nov 01, 2022)
19-39415000-G-A			Uncertain significance (Aug 18, 2022)
19-39415005-C-A			Likely benign (Jun 27, 2023)
19-39415007-C-T		not specified	Uncertain significance (Jun 07, 2024)
19-39415010-T-C		PLEKHG2-related disorder	Likely benign (Jan 25, 2024)
19-39415019-C-T			Uncertain significance (Jul 21, 2022)
19-39415020-C-G			Benign/Likely benign (Feb 01, 2024)
19-39415020-C-T			Likely benign (Nov 14, 2023)
19-39415022-G-A			Benign (Jan 08, 2024)
19-39415032-G-C			Likely benign (Jul 06, 2018)
19-39415037-C-T		not specified	Uncertain significance (Apr 07, 2022)
19-39415040-C-T			Uncertain significance (Jun 16, 2021)
19-39415048-A-G		not specified	Uncertain significance (Mar 06, 2023)
19-39415058-G-A			Uncertain significance (Jan 13, 2022)
19-39415090-C-T		not specified	Uncertain significance (Oct 26, 2022)
19-39415097-G-T		PLEKHG2-related disorder	Likely benign (Dec 15, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
PLEKHG2	protein_coding	protein_coding	ENST00000409794	18	15830

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.36e-9	1.00	125680	0	68	125748	0.000270

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.801	736	800	0.920	0.0000483	8744
Missense in Polyphen		243	267.22	0.90937		2844
Synonymous	0.894	311	332	0.938	0.0000202	3088
Loss of Function	3.94	25	57.2	0.437	0.00000340	599

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000748	0.000734
Ashkenazi Jewish	0.0000994	0.0000992
East Asian	0.000382	0.000381
Finnish	0.0000926	0.0000924
European (Non-Finnish)	0.000297	0.000290
Middle Eastern	0.000382	0.000381
South Asian	0.000268	0.000261
Other	0.000329	0.000326

dbNSFP

Source: dbNSFP

• Function: FUNCTION: May be a transforming oncogene with exchange activity for CDC42 (By similarity). May be a guanine-nucleotide exchange factor (GEF) for RAC1 and CDC42. Activated by the binding to subunits beta and gamma of the heterotrimeric guanine nucleotide- binding protein (G protein) (PubMed:18045877). Involved in the regulation of actin polymerization (PubMed:26573021). {ECO:0000250|UniProtKB:Q6KAU7, ECO:0000269|PubMed:18045877, ECO:0000269|PubMed:26573021}.
• Disease: DISEASE: Leukodystrophy and acquired microcephaly with or without dystonia (LDAMD) [MIM:616763]: An autosomal recessive neurologic disorder characterized by profound mental retardation, dystonia, postnatal microcephaly, and white matter abnormalities consistent with leukodystrophy. {ECO:0000269|PubMed:26573021}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Signaling by GPCR;Signal Transduction;Rho GTPase cycle;Signaling by Rho GTPases;NRAGE signals death through JNK;Death Receptor Signalling;p75 NTR receptor-mediated signalling;G alpha (12/13) signalling events;GPCR downstream signalling;Cell death signalling via NRAGE, NRIF and NADE (Consensus)

Recessive Scores

• pRec: 0.0979

Intolerance Scores

• loftool: 0.407
• rvis_EVS: 0.51
• rvis_percentile_EVS: 80.01

Haploinsufficiency Scores

• pHI: 0.134
• hipred: N
• hipred_score: 0.270
• ghis: 0.474

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.919

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium

Mouse Genome Informatics

• Gene name: Plekhg2

Gene ontology

• Biological process: G protein-coupled receptor signaling pathway;regulation of actin filament polymerization;regulation of Rho protein signal transduction;positive regulation of apoptotic process;regulation of small GTPase mediated signal transduction
• Cellular component: cytosol
• Molecular function: guanyl-nucleotide exchange factor activity;Rho guanyl-nucleotide exchange factor activity