rs796052828

Variant names:

• chrX-100407535-GCTCA-G
• rs796052828
• NM_001184880.2:c.1059_1062delTGAG

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001184880.2(PCDH19):​c.1059_1062delTGAG​(p.Glu354LeufsTer13) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 24)
• Consequence: PCDH19 NM_001184880.2 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 7.84

Genes affected

PCDH19 (HGNC:14270): (protocadherin 19) The protein encoded by this gene is a member of the delta-2 protocadherin subclass of the cadherin superfamily. The encoded protein is thought to be a calcium-dependent cell-adhesion protein that is primarily expressed in the brain. Mutations in this gene on human chromosome X are associated with sporadic infantile epileptic encephalopathy and to a female-restricted form of epilepsy (EFMR; also known as PCDH19RE). Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2017]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-100407535-GCTCA-G is Pathogenic according to our data. Variant chrX-100407535-GCTCA-G is described in ClinVar as [Pathogenic]. Clinvar id is 206351.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCDH19	NM_001184880.2	c.1059_1062delTGAG	p.Glu354LeufsTer13	frameshift_variant	Exon 1 of 6	ENST00000373034.8	NP_001171809.1
PCDH19	NM_001105243.2	c.1059_1062delTGAG	p.Glu354LeufsTer13	frameshift_variant	Exon 1 of 5		NP_001098713.1
PCDH19	NM_020766.3	c.1059_1062delTGAG	p.Glu354LeufsTer13	frameshift_variant	Exon 1 of 5		NP_065817.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCDH19	ENST00000373034.8	c.1059_1062delTGAG	p.Glu354LeufsTer13	frameshift_variant	Exon 1 of 6	1	NM_001184880.2	ENSP00000362125.4
PCDH19	ENST00000255531.8	c.1059_1062delTGAG	p.Glu354LeufsTer13	frameshift_variant	Exon 1 of 5	1		ENSP00000255531.7
PCDH19	ENST00000420881.6	c.1059_1062delTGAG	p.Glu354LeufsTer13	frameshift_variant	Exon 1 of 5	1		ENSP00000400327.2

Frequencies

GnomAD3 genomes Cov.: 24

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 24

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Jun 11, 2012

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is denoted c.1059_1062delTGAG: p.Glu354LeufsX13 (p.E354LfsX13) in exon 1 of the PCDH19 gene (NM_001105243.1). The c.1059_1062delTGAG mutation in the PCDH19 gene causes a frameshift starting with codon Glutamic acid 354, changes this amino acid to a Leucine residue and creates a premature Stop codon at position 13 of the new reading frame, denoted p.Glu354LeufsX13. This mutation is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Although this mutation has not been previously reported to our knowledge, its presence is consistent with a diagnosis of epilepsy and mental retardation limited to females (EFMR). The variant is found in CHILD-EPI panel(s). -

Developmental and epileptic encephalopathy, 9 Pathogenic:1

Mar 16, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Glu354Leufs*13) in the PCDH19 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in PCDH19 are known to be pathogenic (PMID: 21053371). This variant has not been reported in the literature in individuals with PCDH19-related disease. ClinVar contains an entry for this variant (Variation ID: 206351). -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs796052828; hg19: chrX-99662533;