rs740842

chr12-6312329-G-Achr12-6312329-G-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001384598.1(PLEKHG6):c.103G>A(p.Ala35Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.562 in 1,580,040 control chromosomes in the GnomAD database, including 253,835 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.56 (24423 hom., cov: 32)
  • Exomes 𝑓: 0.56 (229412 hom.)
• Consequence: PLEKHG6 NM_001384598.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.297

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

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.6391135E-5).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.596 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLEKHG6	NM_001384598.1	c.103G>A	p.Ala35Thr	missense_variant	2/16	ENST00000684764.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLEKHG6	ENST00000684764.1	c.103G>A	p.Ala35Thr	missense_variant	2/16		NM_001384598.1	P1

Frequencies

GnomAD3 genomes AF: 0.561 AC: 85330 AN: 151968 Hom.: 24393 Cov.: 32

Gnomad AFR AF: 0.602

Gnomad AMI AF: 0.549

Gnomad AMR AF: 0.459

Gnomad ASJ AF: 0.516

Gnomad EAS AF: 0.259

Gnomad SAS AF: 0.416

Gnomad FIN AF: 0.605

Gnomad MID AF: 0.468

Gnomad NFE AF: 0.591

Gnomad OTH AF: 0.513

GnomAD3 exomes AF: 0.513 AC: 112819 AN: 219970 Hom.: 30317 AF XY: 0.514 AC XY: 61759 AN XY: 120226

Gnomad AFR exome AF: 0.594

Gnomad AMR exome AF: 0.398

Gnomad ASJ exome AF: 0.498

Gnomad EAS exome AF: 0.242

Gnomad SAS exome AF: 0.421

Gnomad FIN exome AF: 0.597

Gnomad NFE exome AF: 0.580

Gnomad OTH exome AF: 0.524

GnomAD4 exome AF: 0.562 AC: 802323 AN: 1427954 Hom.: 229412 Cov.: 45 AF XY: 0.559 AC XY: 396896 AN XY: 710088

Gnomad4 AFR exome AF: 0.597

Gnomad4 AMR exome AF: 0.402

Gnomad4 ASJ exome AF: 0.495

Gnomad4 EAS exome AF: 0.268

Gnomad4 SAS exome AF: 0.433

Gnomad4 FIN exome AF: 0.597

Gnomad4 NFE exome AF: 0.587

Gnomad4 OTH exome AF: 0.540

GnomAD4 genome AF: 0.562 AC: 85401 AN: 152086 Hom.: 24423 Cov.: 32 AF XY: 0.557 AC XY: 41431 AN XY: 74330

Gnomad4 AFR AF: 0.602

Gnomad4 AMR AF: 0.457

Gnomad4 ASJ AF: 0.516

Gnomad4 EAS AF: 0.259

Gnomad4 SAS AF: 0.417

Gnomad4 FIN AF: 0.605

Gnomad4 NFE AF: 0.591

Gnomad4 OTH AF: 0.515

Alfa AF: 0.569 Hom.: 52502

Bravo AF: 0.549

TwinsUK AF: 0.582 AC: 2157

ALSPAC AF: 0.593 AC: 2285

ESP6500AA AF: 0.601 AC: 2646

ESP6500EA AF: 0.573 AC: 4925

ExAC AF: 0.518 AC: 62935

Asia WGS AF: 0.349 AC: 1215 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.77	T
BayesDel_noAF	Benign	-0.73
Cadd	Benign	8.0
Dann	Benign	0.95
DEOGEN2	Benign	0.016	T;.;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.020	N
MetaRNN	Benign	0.000026	T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Uncertain	2.0	M;.;M
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.16	N;N;N
REVEL	Benign	0.024
Sift	Uncertain	0.026	D;T;D
Sift4G	Benign	0.065	T;T;T
Polyphen		0.099	B;B;B
Vest4		0.025
MPC		0.13
ClinPred		0.010	T
GERP RS		-4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.038
gMVP		0.44

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: rs740842; hg19: chr12-6421495; COSMIC: COSV50607477; COSMIC: COSV50607477;