19-39414985-C-T

Variant names:

• chr19-39414985-C-T
• rs762298375
• NM_022835.3:c.110-7C>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_022835.3(PLEKHG2):​c.110-7C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000604 in 1,589,072 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00019 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000047 (0 hom.)
• Consequence: PLEKHG2 NM_022835.3 splice_region, intron
• Scores: Splicing: ADA: 0.0005748
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.185
• Publications: 0 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.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BP6: Variant 19-39414985-C-T is Benign according to our data. Variant chr19-39414985-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 762270.Status of the report is criteria_provided_single_submitter, 1 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.110-7C>T		splice_region intron	N/A	NP_073746.2	Q9H7P9-1
	PLEKHG2	NM_001351693.2		c.110-184C>T		intron	N/A	NP_001338622.1	E7ESZ3
	PLEKHG2	NM_001351694.2		c.110-7C>T		splice_region 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.110-7C>T		splice_region intron	N/A	ENSP00000392906.2	Q9H7P9-1
	PLEKHG2	ENST00000942561.1		c.110-7C>T		splice_region intron	N/A	ENSP00000612620.1
	PLEKHG2	ENST00000942562.1		c.110-7C>T		splice_region intron	N/A	ENSP00000612621.1

Frequencies

GnomAD3 genomes AF: 0.000191 AC: 29 AN: 152164 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.000955

GnomAD2 exomes AF: 0.0000810 AC: 18 AN: 222316 AF XY: 0.000115

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000400

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000409

Gnomad OTH exome AF: 0.000182

GnomAD4 exome AF: 0.0000466 AC: 67 AN: 1436908 Hom.: 0 Cov.: 31 AF XY: 0.0000520 AC XY: 37 AN XY: 711738

African (AFR) AF: 0.0000915 AC: 3 AN: 32792

American (AMR) AF: 0.000327 AC: 14 AN: 42786

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24982

East Asian (EAS) AF: 0.00 AC: 0 AN: 38924

South Asian (SAS) AF: 0.00 AC: 0 AN: 83520

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51358

Middle Eastern (MID) AF: 0.000529 AC: 3 AN: 5676

European-Non Finnish (NFE) AF: 0.0000392 AC: 43 AN: 1097642

Other (OTH) AF: 0.0000675 AC: 4 AN: 59228

GnomAD4 genome AF: 0.000191 AC: 29 AN: 152164 Hom.: 0 Cov.: 32 AF XY: 0.000283 AC XY: 21 AN XY: 74328

African (AFR) AF: 0.00 AC: 0 AN: 41422

American (AMR) AF: 0.00157 AC: 24 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

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

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68014

Other (OTH) AF: 0.000955 AC: 2 AN: 2094

Alfa AF: 0.0000489 Hom.: 0

Bravo AF: 0.000147

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
BayesDel_noAF	Benign	-0.69
CADD	Benign	9.8
DANN	Benign	0.89
PhyloP100		-0.18
PromoterAI		-0.00040	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00057
SpliceAI score (max)		0.030		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: rs762298375; hg19: chr19-39905625;