chr19-39415010-T-C

Variant names:

• chr19-39415010-T-C
• rs45441295
• NM_022835.3:c.128T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_022835.3(PLEKHG2):​c.128T>C​(p.Met43Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000388 in 1,597,202 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00063 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00036 (0 hom.)
• Consequence: PLEKHG2 NM_022835.3 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.755
• Publications: 5 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.01963082).
• BP6: Variant 19-39415010-T-C is Benign according to our data. Variant chr19-39415010-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 722867.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.128T>C	p.Met43Thr	missense	Exon 3 of 19	NP_073746.2	Q9H7P9-1
	PLEKHG2	NM_001351694.2		c.128T>C	p.Met43Thr	missense	Exon 3 of 18	NP_001338623.1	Q9H7P9-2
	PLEKHG2	NM_001351693.2		c.110-159T>C		intron	N/A	NP_001338622.1	E7ESZ3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLEKHG2	ENST00000425673.6	TSL:2 MANE Select	c.128T>C	p.Met43Thr	missense	Exon 3 of 19	ENSP00000392906.2	Q9H7P9-1
	PLEKHG2	ENST00000942561.1		c.128T>C	p.Met43Thr	missense	Exon 2 of 18	ENSP00000612620.1
	PLEKHG2	ENST00000942562.1		c.128T>C	p.Met43Thr	missense	Exon 3 of 19	ENSP00000612621.1

Frequencies

GnomAD3 genomes AF: 0.000631 AC: 96 AN: 152164 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00358

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000823

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000441 AC: 100 AN: 226912 AF XY: 0.000435

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000322

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00243

Gnomad NFE exome AF: 0.000471

Gnomad OTH exome AF: 0.000357

GnomAD4 exome AF: 0.000363 AC: 524 AN: 1445038 Hom.: 0 Cov.: 31 AF XY: 0.000380 AC XY: 272 AN XY: 716562

African (AFR) AF: 0.0000303 AC: 1 AN: 33010

American (AMR) AF: 0.00 AC: 0 AN: 43588

Ashkenazi Jewish (ASJ) AF: 0.000273 AC: 7 AN: 25666

East Asian (EAS) AF: 0.0000256 AC: 1 AN: 39038

South Asian (SAS) AF: 0.00 AC: 0 AN: 84544

European-Finnish (FIN) AF: 0.00255 AC: 132 AN: 51754

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5720

European-Non Finnish (NFE) AF: 0.000322 AC: 355 AN: 1102106

Other (OTH) AF: 0.000470 AC: 28 AN: 59612

GnomAD4 genome AF: 0.000631 AC: 96 AN: 152164 Hom.: 1 Cov.: 32 AF XY: 0.000767 AC XY: 57 AN XY: 74340

African (AFR) AF: 0.00 AC: 0 AN: 41436

American (AMR) AF: 0.000131 AC: 2 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00358 AC: 38 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000823 AC: 56 AN: 68010

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000447 Hom.: 0

Bravo AF: 0.000261

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000238 AC: 2

ExAC AF: 0.000397 AC: 48

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	PLEKHG2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.23
CADD	Uncertain	23
DANN	Benign	0.95
DEOGEN2	Benign	0.011	T
Eigen	Benign	0.11
Eigen_PC	Benign	0.095
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.72	T
M_CAP	Uncertain	0.19	D
MetaRNN	Benign	0.020	T
MetaSVM	Benign	-0.49	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		0.76
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-1.5	N
REVEL	Uncertain	0.31
Sift	Benign	0.034	D
Sift4G	Benign	0.12	T
Polyphen		0.93	P
Vest4		0.62
MVP		0.78
ClinPred		0.12	T
GERP RS		3.9
PromoterAI		-0.026	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.32
gMVP		0.31
Mutation Taster		=72/28	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: rs45441295; hg19: chr19-39905650;