19-39423713-G-A

Variant names:

• chr19-39423713-G-A
• rs73930732
• NM_022835.3:c.2600-20G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_022835.3(PLEKHG2):​c.2600-20G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00274 in 1,597,864 control chromosomes in the GnomAD database, including 89 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (41 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (48 hom.)
• Consequence: PLEKHG2 NM_022835.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -4.66
• Publications: 2 publications found

Genes affected

PLEKHG2 (HGNC:29515): (pleckstrin homology and RhoGEF domain containing G2) The protein encoded by this gene is a RhoGTPase that can activate CDC42 by promoting exchange of GDP for GTP on CDC42. The encoded protein is activated by binding to the beta and gamma subunits of heterotrimeric guanine nucleotide-binding protein. Defects in this gene have been associated with leukodystrophy and acquired microcephaly with or without dystonia. [provided by RefSeq, May 2017]

PLEKHG2 Gene-Disease associations (from GenCC):

• leukodystrophy and acquired microcephaly with or without dystonia;

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Illumina, Labcorp Genetics (formerly Invitae)
• epilepsy

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BP6: Variant 19-39423713-G-A is Benign according to our data. Variant chr19-39423713-G-A is described in ClinVar as Benign. ClinVar VariationId is 446058.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0141 (2140/152286) while in subpopulation AFR AF = 0.0483 (2005/41552). AF 95% confidence interval is 0.0465. There are 41 homozygotes in GnomAd4. There are 1017 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 41 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022835.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLEKHG2	NM_022835.3	MANE Select	c.2600-20G>A		intron	N/A	NP_073746.2	Q9H7P9-1
	PLEKHG2	NM_001351693.2		c.2423-20G>A		intron	N/A	NP_001338622.1	E7ESZ3
	PLEKHG2	NM_001351694.2		c.1677+1425G>A		intron	N/A	NP_001338623.1	Q9H7P9-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLEKHG2	ENST00000425673.6	TSL:2 MANE Select	c.2600-20G>A		intron	N/A	ENSP00000392906.2	Q9H7P9-1
	PLEKHG2	ENST00000205135.8	TSL:1	c.2201-20G>A		intron	N/A	ENSP00000205135.3	H7BXC7
	PLEKHG2	ENST00000942561.1		c.2600-20G>A		intron	N/A	ENSP00000612620.1

Frequencies

GnomAD3 genomes AF: 0.0141 AC: 2140 AN: 152168 Hom.: 41 Cov.: 32

Gnomad AFR AF: 0.0484

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00524

Gnomad ASJ AF: 0.00403

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000323

Gnomad OTH AF: 0.00909

GnomAD2 exomes AF: 0.00410 AC: 984 AN: 240096 AF XY: 0.00309

Gnomad AFR exome AF: 0.0491

Gnomad AMR exome AF: 0.00306

Gnomad ASJ exome AF: 0.00494

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000267

Gnomad OTH exome AF: 0.00206

GnomAD4 exome AF: 0.00155 AC: 2235 AN: 1445578 Hom.: 48 Cov.: 81 AF XY: 0.00141 AC XY: 1008 AN XY: 716944

African (AFR) AF: 0.0468 AC: 1556 AN: 33218

American (AMR) AF: 0.00322 AC: 141 AN: 43726

Ashkenazi Jewish (ASJ) AF: 0.00480 AC: 119 AN: 24798

East Asian (EAS) AF: 0.00 AC: 0 AN: 39524

South Asian (SAS) AF: 0.0000716 AC: 6 AN: 83846

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52760

Middle Eastern (MID) AF: 0.00228 AC: 13 AN: 5690

European-Non Finnish (NFE) AF: 0.000165 AC: 182 AN: 1102414

Other (OTH) AF: 0.00366 AC: 218 AN: 59602

GnomAD4 genome AF: 0.0141 AC: 2140 AN: 152286 Hom.: 41 Cov.: 32 AF XY: 0.0137 AC XY: 1017 AN XY: 74446

African (AFR) AF: 0.0483 AC: 2005 AN: 41552

American (AMR) AF: 0.00523 AC: 80 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00403 AC: 14 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000323 AC: 22 AN: 68030

Other (OTH) AF: 0.00900 AC: 19 AN: 2112

Alfa AF: 0.00687 Hom.: 4

Bravo AF: 0.0158

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.015
DANN	Benign	0.51
PhyloP100		-4.7
PromoterAI		-0.034	Neutral
Mutation Taster		=100/0	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: rs73930732; hg19: chr19-39914353;