chrX-136675018-C-G

Variant names:

• chrX-136675018-C-G
• rs1426557239
• NM_004840.3:c.2024G>C

Variant summary

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

The NM_004840.3(ARHGEF6):​c.2024G>C​(p.Gly675Ala) 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. 14/20 in silico tools predict 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: 22)
• Consequence: ARHGEF6 NM_004840.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.24

Genes affected

ARHGEF6 (HGNC:685): (Rac/Cdc42 guanine nucleotide exchange factor 6) Rho GTPases play a fundamental role in numerous cellular processes that are initiated by extracellular stimuli that work through G protein coupled receptors. The encoded protein belongs to a family of cytoplasmic proteins that activate the Ras-like family of Rho proteins by exchanging bound GDP for GTP. It may form a complex with G proteins and stimulate Rho-dependent signals. This protein is activated by PI3-kinase. Mutations in this gene can cause X-chromosomal non-specific cognitive disability. [provided by RefSeq, Jul 2008]

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=0.093486905).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARHGEF6	NM_004840.3	c.2024G>C	p.Gly675Ala	missense_variant	Exon 19 of 22	ENST00000250617.7	NP_004831.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARHGEF6	ENST00000250617.7	c.2024G>C	p.Gly675Ala	missense_variant	Exon 19 of 22	1	NM_004840.3	ENSP00000250617.6
ARHGEF6	ENST00000370622.5	c.1562G>C	p.Gly521Ala	missense_variant	Exon 18 of 21	1		ENSP00000359656.1
ARHGEF6	ENST00000370620.5	c.1562G>C	p.Gly521Ala	missense_variant	Exon 18 of 21	2		ENSP00000359654.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 22

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	19
DANN	Benign	0.90
DEOGEN2	Benign	0.11	.;.;T
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.72	.;T;T
M_CAP	Uncertain	0.088	D
MetaRNN	Benign	0.093	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.34	.;.;N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	0.20	N;N;N
REVEL	Benign	0.052
Sift	Benign	0.86	T;T;T
Sift4G	Benign	0.43	T;T;T
Polyphen		0.0010	.;.;B
Vest4		0.065
MutPred		0.13		.;.;Loss of loop (P = 0.0804);
MVP		0.46
MPC		0.31
ClinPred		0.46	T
GERP RS		3.6
Varity_R		0.16
gMVP		0.093

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

LitVar

Other links and lift over

dbSNP: rs1426557239; hg19: chrX-135757177;