rs756414485
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001184880.2(PCDH19):c.2656C>T(p.Arg886Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.000000929 in 1,076,197 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. 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)
Exomes 𝑓: 9.3e-7 ( 0 hom. 0 hem. )
Consequence
PCDH19
NM_001184880.2 stop_gained
NM_001184880.2 stop_gained
Scores
2
2
1
Clinical Significance
Conservation
PhyloP100: 4.89
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-100350665-G-A is Pathogenic according to our data. Variant chrX-100350665-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 206341.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-100350665-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PCDH19 | NM_001184880.2 | c.2656C>T | p.Arg886Ter | stop_gained | 4/6 | ENST00000373034.8 | |
PCDH19 | NM_001105243.2 | c.2515C>T | p.Arg839Ter | stop_gained | 3/5 | ||
PCDH19 | NM_020766.3 | c.2515C>T | p.Arg839Ter | stop_gained | 3/5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PCDH19 | ENST00000373034.8 | c.2656C>T | p.Arg886Ter | stop_gained | 4/6 | 1 | NM_001184880.2 | A1 | |
PCDH19 | ENST00000255531.8 | c.2515C>T | p.Arg839Ter | stop_gained | 3/5 | 1 | P5 | ||
PCDH19 | ENST00000420881.6 | c.2515C>T | p.Arg839Ter | stop_gained | 3/5 | 1 | A1 | ||
PCDH19 | ENST00000636150.1 | c.157C>T | p.Arg53Ter | stop_gained | 3/3 | 5 |
Frequencies
GnomAD3 genomes ? Cov.: 24
GnomAD3 genomes
?
Cov.:
24
GnomAD4 exome AF: 9.29e-7 AC: 1AN: 1076197Hom.: 0 Cov.: 25 AF XY: 0.00 AC XY: 0AN XY: 344305
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GnomAD4 genome ? Cov.: 24
GnomAD4 genome
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Cov.:
24
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 14, 2019 | Previously reported to segregate with epilepsy in several females from a single family who had febrile, generalized, and/or focal seizures, one of whom also had cognitive delay (Depienne et al., 2011); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 23334464, 22267240, 25525159, 21053371, 27179713, 23712037, 22633638, 29377098) - |
Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Feb 16, 2017 | - - |
Developmental and epileptic encephalopathy, 9 Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 16, 2024 | This sequence change creates a premature translational stop signal (p.Arg886*) 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 generalized epilepsy with febrile seizures plus (PMID: 21053371). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 206341). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Mar 25, 2024 | - - |
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 14, 2019 | The p.R886* pathogenic mutation (also known as c.2656C>T), located in coding exon 4 of the PCDH19 gene, results from a C to T substitution at nucleotide position 2656. This changes the amino acid from an arginine to a stop codon within coding exon 4. This variant has been reported in 5 females with seizures, including one family with 4 affected women (Depienne C et al. Hum. Mutat., 2011 Jan;32:E1959-75; Smith L et al. Epilepsia, 2018 03;59:679-689). 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. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
A;A;A
Vest4
GERP RS
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