rs796052828
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001184880.2(PCDH19):c.1059_1062del(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 (★★). Synonymous variant affecting the same amino acid position (i.e. S353S) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 24)
Consequence
PCDH19
NM_001184880.2 frameshift
NM_001184880.2 frameshift
Scores
Not classified
Clinical Significance
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]
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ACMG classification
Classification made for transcript
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/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PCDH19 | NM_001184880.2 | c.1059_1062del | p.Glu354LeufsTer13 | frameshift_variant | 1/6 | ENST00000373034.8 | |
PCDH19 | NM_001105243.2 | c.1059_1062del | p.Glu354LeufsTer13 | frameshift_variant | 1/5 | ||
PCDH19 | NM_020766.3 | c.1059_1062del | p.Glu354LeufsTer13 | frameshift_variant | 1/5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PCDH19 | ENST00000373034.8 | c.1059_1062del | p.Glu354LeufsTer13 | frameshift_variant | 1/6 | 1 | NM_001184880.2 | A1 | |
PCDH19 | ENST00000255531.8 | c.1059_1062del | p.Glu354LeufsTer13 | frameshift_variant | 1/5 | 1 | P5 | ||
PCDH19 | ENST00000420881.6 | c.1059_1062del | p.Glu354LeufsTer13 | frameshift_variant | 1/5 | 1 | A1 |
Frequencies
GnomAD3 genomes ? Cov.: 24
GnomAD3 genomes
?
Cov.:
24
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome ? Cov.: 24
GnomAD4 genome
?
Cov.:
24
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 11, 2012 | 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
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Mar 16, 2019 | 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). This variant is not present in population databases (ExAC no frequency). 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. - |
Computational scores
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Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at