rs1555984453
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_001184880.2(PCDH19):c.2453del(p.Gln818ArgfsTer16) variant causes a frameshift change. 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: 23)
Consequence
PCDH19
NM_001184880.2 frameshift
NM_001184880.2 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 4.50
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 12 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-100402686-CT-C is Pathogenic according to our data. Variant chrX-100402686-CT-C is described in ClinVar as [Pathogenic]. Clinvar id is 465300.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PCDH19 | NM_001184880.2 | c.2453del | p.Gln818ArgfsTer16 | frameshift_variant | 3/6 | ENST00000373034.8 | |
PCDH19 | NM_001105243.2 | c.2312del | p.Gln771ArgfsTer16 | frameshift_variant | 2/5 | ||
PCDH19 | NM_020766.3 | c.2312del | p.Gln771ArgfsTer16 | frameshift_variant | 2/5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PCDH19 | ENST00000373034.8 | c.2453del | p.Gln818ArgfsTer16 | frameshift_variant | 3/6 | 1 | NM_001184880.2 | A1 | |
PCDH19 | ENST00000255531.8 | c.2312del | p.Gln771ArgfsTer16 | frameshift_variant | 2/5 | 1 | P5 | ||
PCDH19 | ENST00000420881.6 | c.2312del | p.Gln771ArgfsTer16 | frameshift_variant | 2/5 | 1 | A1 | ||
PCDH19 | ENST00000636150.1 | c.66-112del | intron_variant | 5 |
Frequencies
GnomAD3 genomes ? Cov.: 23
GnomAD3 genomes
?
Cov.:
23
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome ? Cov.: 23
GnomAD4 genome
?
Cov.:
23
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Developmental and epileptic encephalopathy, 9 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 14, 2022 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 465300). This variant has not been reported in the literature in individuals affected with PCDH19-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln818Argfs*16) in the PCDH19 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PCDH19 are known to be pathogenic (PMID: 21053371). - |
Computational scores
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Prediction
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