12-6312329-G-C

Variant names:

• chr12-6312329-G-C
• rs740842
• NM_001384598.1:c.103G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001384598.1(PLEKHG6):​c.103G>C​(p.Ala35Pro) 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. 16/22 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: 32)
• Consequence: PLEKHG6 NM_001384598.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.297
• Publications: 32 publications found

Genes affected

PLEKHG6 (HGNC:25562): (pleckstrin homology and RhoGEF domain containing G6) Predicted to enable guanyl-nucleotide exchange factor activity. Predicted to be involved in regulation of small GTPase mediated signal transduction. Located in cell junction and centrosome. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.050909877).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001384598.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLEKHG6	NM_001384598.1	MANE Select	c.103G>C	p.Ala35Pro	missense	Exon 2 of 16	NP_001371527.1
	PLEKHG6	NM_001384604.1		c.103G>C	p.Ala35Pro	missense	Exon 2 of 16	NP_001371533.1
	PLEKHG6	NM_001144856.2		c.103G>C	p.Ala35Pro	missense	Exon 2 of 16	NP_001138328.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLEKHG6	ENST00000684764.1	MANE Select	c.103G>C	p.Ala35Pro	missense	Exon 2 of 16	ENSP00000506982.1
	PLEKHG6	ENST00000011684.11	TSL:1	c.103G>C	p.Ala35Pro	missense	Exon 2 of 16	ENSP00000011684.7
	PLEKHG6	ENST00000536531.5	TSL:1	c.103G>C	p.Ala35Pro	missense	Exon 2 of 12	ENSP00000442836.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 45

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	5.7
DANN	Benign	0.83
DEOGEN2	Benign	0.010	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.020	N
LIST_S2	Benign	0.56	T
M_CAP	Benign	0.0051	T
MetaRNN	Benign	0.051	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.81	L
PhyloP100		-0.30
PrimateAI	Benign	0.32	T
PROVEAN	Benign	0.43	N
REVEL	Benign	0.010
Sift	Benign	0.33	T
Sift4G	Benign	0.27	T
Polyphen		0.0	B
Vest4		0.092
MutPred		0.24		Gain of catalytic residue at L38 (P = 0)
MVP		0.040
MPC		0.18
ClinPred		0.080	T
GERP RS		-4.3
PromoterAI		-0.017	Neutral
Varity_R		0.052
gMVP		0.43
Mutation Taster		=90/10	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: rs740842; hg19: chr12-6421495;