rs1555985416
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001184880.2(PCDH19):c.879_880insACCCG(p.His294ThrfsTer13) variant causes a frameshift change involving the alteration of a non-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. P293P) 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: -2.08
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-100407718-G-GCGGGT is Pathogenic according to our data. Variant chrX-100407718-G-GCGGGT is described in ClinVar as [Pathogenic]. Clinvar id is 504290.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.879_880insACCCG | p.His294ThrfsTer13 | frameshift_variant | 1/6 | ENST00000373034.8 | |
PCDH19 | NM_001105243.2 | c.879_880insACCCG | p.His294ThrfsTer13 | frameshift_variant | 1/5 | ||
PCDH19 | NM_020766.3 | c.879_880insACCCG | p.His294ThrfsTer13 | frameshift_variant | 1/5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PCDH19 | ENST00000373034.8 | c.879_880insACCCG | p.His294ThrfsTer13 | frameshift_variant | 1/6 | 1 | NM_001184880.2 | A1 | |
PCDH19 | ENST00000255531.8 | c.879_880insACCCG | p.His294ThrfsTer13 | frameshift_variant | 1/5 | 1 | P5 | ||
PCDH19 | ENST00000420881.6 | c.879_880insACCCG | p.His294ThrfsTer13 | frameshift_variant | 1/5 | 1 | A1 |
Frequencies
GnomAD3 genomes ? Cov.: 24
GnomAD3 genomes
?
Cov.:
24
GnomAD4 exome Cov.: 33
GnomAD4 exome
Cov.:
33
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 | Feb 02, 2018 | The c.875_879dupACCCG variant in the PCDH19 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The c.875_879dupACCCG variant causes a frameshift starting with codon Histidine 294, changes this amino acid to a Threonine residue, and creates a premature Stop codon at position 13 of the new reading frame, denoted p.His294ThrfsX13. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.875_879dupACCCG variant is not observed in large population cohorts (Lek et al., 2016). We interpret c.875_879dupACCCG as a pathogenic variant. - |
Developmental and epileptic encephalopathy, 9 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 28, 2018 | 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. This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.His294Thrfs*13) in the PCDH19 gene. It is expected to result in an absent or disrupted protein product. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at