rs1555985427
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001184880.2(PCDH19):c.859G>T(p.Glu287*) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 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 stop_gained
NM_001184880.2 stop_gained
Scores
2
2
1
Clinical Significance
Conservation
PhyloP100: 3.84
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-100407739-C-A is Pathogenic according to our data. Variant chrX-100407739-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 447921.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-100407739-C-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PCDH19 | NM_001184880.2 | c.859G>T | p.Glu287* | stop_gained | 1/6 | ENST00000373034.8 | NP_001171809.1 | |
PCDH19 | NM_001105243.2 | c.859G>T | p.Glu287* | stop_gained | 1/5 | NP_001098713.1 | ||
PCDH19 | NM_020766.3 | c.859G>T | p.Glu287* | stop_gained | 1/5 | NP_065817.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
PCDH19 | ENST00000373034.8 | c.859G>T | p.Glu287* | stop_gained | 1/6 | 1 | NM_001184880.2 | ENSP00000362125.4 | ||
PCDH19 | ENST00000255531.8 | c.859G>T | p.Glu287* | stop_gained | 1/5 | 1 | ENSP00000255531.7 | |||
PCDH19 | ENST00000420881.6 | c.859G>T | p.Glu287* | stop_gained | 1/5 | 1 | ENSP00000400327.2 |
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 | Athena Diagnostics | Feb 16, 2017 | - - |
Developmental and epileptic encephalopathy, 9 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 12, 2023 | This sequence change creates a premature translational stop signal (p.Glu287*) 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). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with clinical features of PCDH19-related conditions (PMID: 19214208). ClinVar contains an entry for this variant (Variation ID: 447921). For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
FATHMM_MKL
Uncertain
D
Vest4
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at