NM_022835.3:c.110-7C>A

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_022835.3(PLEKHG2):​c.110-7C>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000696 in 1,436,908 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: PLEKHG2 NM_022835.3 splice_region, intron
• Scores: Splicing: ADA: 0.1495
• Clinical Significance: Not reported in ClinVar
• 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 -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).

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>A		splice_region intron	N/A	NP_073746.2	Q9H7P9-1
	PLEKHG2	NM_001351693.2		c.110-184C>A		intron	N/A	NP_001338622.1	E7ESZ3
	PLEKHG2	NM_001351694.2		c.110-7C>A		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>A		splice_region intron	N/A	ENSP00000392906.2	Q9H7P9-1
	PLEKHG2	ENST00000942561.1		c.110-7C>A		splice_region intron	N/A	ENSP00000612620.1
	PLEKHG2	ENST00000942562.1		c.110-7C>A		splice_region intron	N/A	ENSP00000612621.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.96e-7 AC: 1 AN: 1436908 Hom.: 0 Cov.: 31 AF XY: 0.00000141 AC XY: 1 AN XY: 711738

African (AFR) AF: 0.00 AC: 0 AN: 32792

American (AMR) AF: 0.00 AC: 0 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: 0.00 AC: 0 AN: 5676

European-Non Finnish (NFE) AF: 9.11e-7 AC: 1 AN: 1097642

Other (OTH) AF: 0.00 AC: 0 AN: 59228

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	11
DANN	Benign	0.90
PhyloP100		-0.18
PromoterAI		0.015	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.15
SpliceAI score (max)		0.12		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;