rs576060981

Variant names:

• chr19-39414128-C-G
• rs576060981
• NM_022835.3:c.42C>G

Your query was ambiguous. Multiple possible variants found:

• chr19-39414128-C-G
• chr19-39414128-C-T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP6_Moderate BS2

The NM_022835.3(PLEKHG2):​c.42C>G​(p.Ser14Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000436 in 1,551,604 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00046 (13 hom.)
• Consequence: PLEKHG2 NM_022835.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.29
• Publications: 1 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: Likely_benign. The variant received -6 ACMG points.

• BP6: Variant 19-39414128-C-G is Benign according to our data. Variant chr19-39414128-C-G is described in ClinVar as Likely_benign. ClinVar VariationId is 722233.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAdExome4 at 13 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.42C>G	p.Ser14Arg	missense	Exon 2 of 19	NP_073746.2	Q9H7P9-1
	PLEKHG2	NM_001351693.2		c.42C>G	p.Ser14Arg	missense	Exon 2 of 20	NP_001338622.1	E7ESZ3
	PLEKHG2	NM_001351694.2		c.42C>G	p.Ser14Arg	missense	Exon 2 of 18	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.42C>G	p.Ser14Arg	missense	Exon 2 of 19	ENSP00000392906.2	Q9H7P9-1
	PLEKHG2	ENST00000942561.1		c.42C>G	p.Ser14Arg	missense	Exon 1 of 18	ENSP00000612620.1
	PLEKHG2	ENST00000942562.1		c.42C>G	p.Ser14Arg	missense	Exon 2 of 19	ENSP00000612621.1

Frequencies

GnomAD3 genomes AF: 0.000250 AC: 38 AN: 152242 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00786

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00106 AC: 165 AN: 155820 AF XY: 0.00152

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000166

Gnomad OTH exome AF: 0.000228

GnomAD4 exome AF: 0.000457 AC: 640 AN: 1399244 Hom.: 13 Cov.: 30 AF XY: 0.000674 AC XY: 465 AN XY: 690152

African (AFR) AF: 0.00 AC: 0 AN: 31596

American (AMR) AF: 0.00 AC: 0 AN: 35702

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25182

East Asian (EAS) AF: 0.00 AC: 0 AN: 35736

South Asian (SAS) AF: 0.00771 AC: 611 AN: 79232

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49204

Middle Eastern (MID) AF: 0.000351 AC: 2 AN: 5696

European-Non Finnish (NFE) AF: 0.00000278 AC: 3 AN: 1078894

Other (OTH) AF: 0.000414 AC: 24 AN: 58002

GnomAD4 genome AF: 0.000236 AC: 36 AN: 152360 Hom.: 0 Cov.: 32 AF XY: 0.000336 AC XY: 25 AN XY: 74510

African (AFR) AF: 0.00 AC: 0 AN: 41580

American (AMR) AF: 0.00 AC: 0 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00745 AC: 36 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.0000279 Hom.: 0

Bravo AF: 0.0000416

ExAC AF: 0.00205 AC: 53

Asia WGS AF: 0.00318 AC: 12 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.33
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0050	T
Eigen	Benign	0.098
Eigen_PC	Benign	0.13
FATHMM_MKL	Benign	0.56	D
LIST_S2	Benign	0.85	T
MetaRNN	Benign	0.0056	T
MetaSVM	Benign	-0.55	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		1.3
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.065
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.98	D
Vest4		0.20
MutPred		0.21		Loss of ubiquitination at K12 (P = 0.0116)
MVP		0.82
ClinPred		0.15	T
GERP RS		4.3
PromoterAI		0.063	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.20
gMVP		0.53
Mutation Taster		=85/15	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.25		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.25		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs576060981; hg19: chr19-39904768;