chrX-100296318-CTT-C
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PVS1_ModerateBS2
The NM_001184880.2(PCDH19):c.3404_3405delAA(p.Lys1135ArgfsTer28) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000268 in 111,942 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_001184880.2 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PCDH19 | NM_001184880.2 | c.3404_3405delAA | p.Lys1135ArgfsTer28 | frameshift_variant | Exon 6 of 6 | ENST00000373034.8 | NP_001171809.1 | |
PCDH19 | NM_001105243.2 | c.3263_3264delAA | p.Lys1088ArgfsTer28 | frameshift_variant | Exon 5 of 5 | NP_001098713.1 | ||
PCDH19 | NM_020766.3 | c.3260_3261delAA | p.Lys1087ArgfsTer28 | frameshift_variant | Exon 5 of 5 | NP_065817.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
PCDH19 | ENST00000373034.8 | c.3404_3405delAA | p.Lys1135ArgfsTer28 | frameshift_variant | Exon 6 of 6 | 1 | NM_001184880.2 | ENSP00000362125.4 | ||
PCDH19 | ENST00000255531.8 | c.3263_3264delAA | p.Lys1088ArgfsTer28 | frameshift_variant | Exon 5 of 5 | 1 | ENSP00000255531.7 | |||
PCDH19 | ENST00000420881.6 | c.3260_3261delAA | p.Lys1087ArgfsTer28 | frameshift_variant | Exon 5 of 5 | 1 | ENSP00000400327.2 | |||
PCDH19 | ENST00000464981.1 | n.-20_-19delAA | upstream_gene_variant | 3 | ENSP00000479805.1 |
Frequencies
GnomAD3 genomes AF: 0.0000268 AC: 3AN: 111942Hom.: 0 Cov.: 22 AF XY: 0.0000586 AC XY: 2AN XY: 34110
GnomAD4 genome AF: 0.0000268 AC: 3AN: 111942Hom.: 0 Cov.: 22 AF XY: 0.0000586 AC XY: 2AN XY: 34110
ClinVar
Submissions by phenotype
Developmental and epileptic encephalopathy, 9 Uncertain:2
This sequence change results in a frameshift in the PCDH19 gene (p.Lys1135Argfs*28). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 14 amino acid(s) of the PCDH19 protein and extend the protein by 13 additional amino acid residues. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. ClinVar contains an entry for this variant (Variation ID: 804048). This variant is also known as c.3263_3264delAA (p.Lys1088ArgfsX28). This frameshift has been observed in individual(s) with developmental and epileptic encephalopathy (PMID: 31054490). This variant is present in population databases (no rsID available, gnomAD 0.02%). -
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not provided Uncertain:1
De novo variant identified in the hemizygous state in a male with developmental delay, microcephaly, and intractable seizures, however pathogenic variants in the PCDH19 gene are inherited in an unusual X-linked manner and hemizygous male carriers are typically unaffected (PMID: 31054490); Frameshift variant predicted to result in abnormal protein length as the last 14 amino acids are replaced with 27 different amino acids; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31054490, 33057194) -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at