12-6326405-A-G

Variant names:

• chr12-6326405-A-G
• rs10849441
• NM_001384598.1:c.1525-23A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001384598.1(PLEKHG6):​c.1525-23A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.45 in 1,589,732 control chromosomes in the GnomAD database, including 166,781 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.40 (12926 hom., cov: 32)
  • Exomes 𝑓: 0.46 (153855 hom.)
• Consequence: PLEKHG6 NM_001384598.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.255
• Publications: 14 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: This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 1 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.48 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.1525-23A>G		intron	N/A	NP_001371527.1
	PLEKHG6	NM_001384604.1		c.1573-23A>G		intron	N/A	NP_001371533.1
	PLEKHG6	NM_001144856.2		c.1525-23A>G		intron	N/A	NP_001138328.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLEKHG6	ENST00000684764.1	MANE Select	c.1525-23A>G		intron	N/A	ENSP00000506982.1
	PLEKHG6	ENST00000011684.11	TSL:1	c.1525-23A>G		intron	N/A	ENSP00000011684.7
	PLEKHG6	ENST00000304581.8	TSL:1	c.115-23A>G		intron	N/A	ENSP00000304640.8

Frequencies

GnomAD3 genomes AF: 0.397 AC: 60251 AN: 151694 Hom.: 12919 Cov.: 32

Gnomad AFR AF: 0.246

Gnomad AMI AF: 0.404

Gnomad AMR AF: 0.364

Gnomad ASJ AF: 0.411

Gnomad EAS AF: 0.262

Gnomad SAS AF: 0.324

Gnomad FIN AF: 0.582

Gnomad MID AF: 0.354

Gnomad NFE AF: 0.484

Gnomad OTH AF: 0.378

GnomAD2 exomes AF: 0.414 AC: 102975 AN: 248920 AF XY: 0.417

Gnomad AFR exome AF: 0.254

Gnomad AMR exome AF: 0.333

Gnomad ASJ exome AF: 0.406

Gnomad EAS exome AF: 0.254

Gnomad FIN exome AF: 0.572

Gnomad NFE exome AF: 0.478

Gnomad OTH exome AF: 0.428

GnomAD4 exome AF: 0.456 AC: 655064 AN: 1437920 Hom.: 153855 Cov.: 28 AF XY: 0.454 AC XY: 325359 AN XY: 716776

African (AFR) AF: 0.238 AC: 7877 AN: 33056

American (AMR) AF: 0.332 AC: 14764 AN: 44460

Ashkenazi Jewish (ASJ) AF: 0.403 AC: 10469 AN: 25966

East Asian (EAS) AF: 0.279 AC: 11030 AN: 39516

South Asian (SAS) AF: 0.344 AC: 29479 AN: 85772

European-Finnish (FIN) AF: 0.575 AC: 30558 AN: 53170

Middle Eastern (MID) AF: 0.370 AC: 2118 AN: 5726

European-Non Finnish (NFE) AF: 0.480 AC: 523280 AN: 1090638

Other (OTH) AF: 0.428 AC: 25489 AN: 59616

GnomAD4 genome AF: 0.397 AC: 60273 AN: 151812 Hom.: 12926 Cov.: 32 AF XY: 0.400 AC XY: 29658 AN XY: 74144

African (AFR) AF: 0.246 AC: 10192 AN: 41486

American (AMR) AF: 0.363 AC: 5537 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.411 AC: 1426 AN: 3468

East Asian (EAS) AF: 0.262 AC: 1354 AN: 5166

South Asian (SAS) AF: 0.324 AC: 1562 AN: 4816

European-Finnish (FIN) AF: 0.582 AC: 6107 AN: 10490

Middle Eastern (MID) AF: 0.346 AC: 101 AN: 292

European-Non Finnish (NFE) AF: 0.484 AC: 32825 AN: 67828

Other (OTH) AF: 0.382 AC: 805 AN: 2110

Alfa AF: 0.442 Hom.: 28790

Bravo AF: 0.370

Asia WGS AF: 0.303 AC: 1055 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	1.9
DANN	Benign	0.45
PhyloP100		-0.26
BranchPoint Hunter		1.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs10849441; hg19: chr12-6435571; COSMIC: COSV50598978; COSMIC: COSV50598978;