rs758946412
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001184880.2(PCDH19):βc.1091delβ(p.Pro364ArgfsTer4) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000911 in 1,097,202 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. Variant has been reported in ClinVar as Pathogenic (β β ). Synonymous variant affecting the same amino acid position (i.e. P364P) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_001184880.2 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PCDH19 | NM_001184880.2 | c.1091del | p.Pro364ArgfsTer4 | frameshift_variant | 1/6 | ENST00000373034.8 | |
PCDH19 | NM_001105243.2 | c.1091del | p.Pro364ArgfsTer4 | frameshift_variant | 1/5 | ||
PCDH19 | NM_020766.3 | c.1091del | p.Pro364ArgfsTer4 | frameshift_variant | 1/5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PCDH19 | ENST00000373034.8 | c.1091del | p.Pro364ArgfsTer4 | frameshift_variant | 1/6 | 1 | NM_001184880.2 | A1 | |
PCDH19 | ENST00000255531.8 | c.1091del | p.Pro364ArgfsTer4 | frameshift_variant | 1/5 | 1 | P5 | ||
PCDH19 | ENST00000420881.6 | c.1091del | p.Pro364ArgfsTer4 | frameshift_variant | 1/5 | 1 | A1 |
Frequencies
GnomAD3 genomes ? Cov.: 24
GnomAD4 exome AF: 9.11e-7 AC: 1AN: 1097202Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 362808
GnomAD4 genome ? Cov.: 24
ClinVar
Submissions by phenotype
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 05, 2016 | The c.1091delC pathogenic mutation, located in coding exon 1 of the PCDH19 gene, results from a deletion of one nucleotide at nucleotide position 1091, causing a translational frameshift with a predicted alternate stop codon. This variant has been reported de novo in an individual with epileptic encephalopathy (van Harssel JJ et al. Neurogenetics, 2013 Feb;14:23-34). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. - |
Developmental and epileptic encephalopathy, 9 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 27, 2023 | This sequence change creates a premature translational stop signal (p.Pro364Argfs*4) 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). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with PCDH19-related disease (PMID: 23334464, 27527380). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 589939). For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at