12-6312329-G-A

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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. 14/21 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: 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
• 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: Benign. The variant received -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.

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>A	p.Ala35Thr	missense	Exon 2 of 16	NP_001371527.1
	PLEKHG6	NM_001384604.1		c.103G>A	p.Ala35Thr	missense	Exon 2 of 16	NP_001371533.1
	PLEKHG6	NM_001144856.2		c.103G>A	p.Ala35Thr	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>A	p.Ala35Thr	missense	Exon 2 of 16	ENSP00000506982.1
	PLEKHG6	ENST00000011684.11	TSL:1	c.103G>A	p.Ala35Thr	missense	Exon 2 of 16	ENSP00000011684.7
	PLEKHG6	ENST00000536531.5	TSL:1	c.103G>A	p.Ala35Thr	missense	Exon 2 of 12	ENSP00000442836.1

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

GnomAD2 exomes AF: 0.513 AC: 112819 AN: 219970 AF XY: 0.514

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 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

African (AFR) AF: 0.597 AC: 18359 AN: 30768

American (AMR) AF: 0.402 AC: 15248 AN: 37894

Ashkenazi Jewish (ASJ) AF: 0.495 AC: 12389 AN: 25034

East Asian (EAS) AF: 0.268 AC: 9951 AN: 37128

South Asian (SAS) AF: 0.433 AC: 35087 AN: 81080

European-Finnish (FIN) AF: 0.597 AC: 31660 AN: 53058

Middle Eastern (MID) AF: 0.487 AC: 2745 AN: 5632

European-Non Finnish (NFE) AF: 0.587 AC: 645009 AN: 1098326

Other (OTH) AF: 0.540 AC: 31875 AN: 59034

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

African (AFR) AF: 0.602 AC: 24993 AN: 41494

American (AMR) AF: 0.457 AC: 6993 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.516 AC: 1787 AN: 3466

East Asian (EAS) AF: 0.259 AC: 1340 AN: 5170

South Asian (SAS) AF: 0.417 AC: 2011 AN: 4822

European-Finnish (FIN) AF: 0.605 AC: 6390 AN: 10568

Middle Eastern (MID) AF: 0.466 AC: 137 AN: 294

European-Non Finnish (NFE) AF: 0.591 AC: 40165 AN: 67968

Other (OTH) AF: 0.515 AC: 1085 AN: 2108

Alfa AF: 0.567 Hom.: 78745

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 v4.9

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
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.020	N
LIST_S2	Benign	0.53	T
MetaRNN	Benign	0.000026	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		-0.30
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.16	N
REVEL	Benign	0.024
Sift	Uncertain	0.026	D
Sift4G	Benign	0.065	T
Polyphen		0.099	B
Vest4		0.025
MPC		0.13
ClinPred		0.010	T
GERP RS		-4.3
PromoterAI		0.010	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.038
gMVP		0.44
Mutation Taster		=100/0	polymorphism (auto)

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; COSMIC: COSV50607477; COSMIC: COSV50607477;