19-39414128-C-T

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP7

The NM_022835.3(PLEKHG2):​c.42C>T​(p.Ser14Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000357 in 1,399,244 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000036 (0 hom.)
• Consequence: PLEKHG2 NM_022835.3 synonymous
• Clinical Significance: Not reported in ClinVar
• 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 -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP7: Synonymous conserved (PhyloP=1.29 with no splicing effect.

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>T	p.Ser14Ser	synonymous	Exon 2 of 19	NP_073746.2	Q9H7P9-1
	PLEKHG2	NM_001351693.2		c.42C>T	p.Ser14Ser	synonymous	Exon 2 of 20	NP_001338622.1	E7ESZ3
	PLEKHG2	NM_001351694.2		c.42C>T	p.Ser14Ser	synonymous	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>T	p.Ser14Ser	synonymous	Exon 2 of 19	ENSP00000392906.2	Q9H7P9-1
	PLEKHG2	ENST00000942561.1		c.42C>T	p.Ser14Ser	synonymous	Exon 1 of 18	ENSP00000612620.1
	PLEKHG2	ENST00000942562.1		c.42C>T	p.Ser14Ser	synonymous	Exon 2 of 19	ENSP00000612621.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000128 AC: 2 AN: 155820 AF XY: 0.0000242

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: 0.0000332

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000357 AC: 5 AN: 1399244 Hom.: 0 Cov.: 30 AF XY: 0.00000724 AC XY: 5 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: 0.00 AC: 0 AN: 79232

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5696

European-Non Finnish (NFE) AF: 0.00000463 AC: 5 AN: 1078894

Other (OTH) AF: 0.00 AC: 0 AN: 58002

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000279 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	12
DANN	Benign	0.87
PhyloP100		1.3
PromoterAI		0.023	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6

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: rs576060981; hg19: chr19-39904768;