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_3405del(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 (★★). Synonymous variant affecting the same amino acid position (i.e. K1135K) has been classified as Likely benign.
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/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PCDH19 | NM_001184880.2 | c.3404_3405del | p.Lys1135ArgfsTer28 | frameshift_variant | 6/6 | ENST00000373034.8 | |
PCDH19 | NM_001105243.2 | c.3263_3264del | p.Lys1088ArgfsTer28 | frameshift_variant | 5/5 | ||
PCDH19 | NM_020766.3 | c.3260_3261del | p.Lys1087ArgfsTer28 | frameshift_variant | 5/5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PCDH19 | ENST00000373034.8 | c.3404_3405del | p.Lys1135ArgfsTer28 | frameshift_variant | 6/6 | 1 | NM_001184880.2 | A1 | |
PCDH19 | ENST00000255531.8 | c.3263_3264del | p.Lys1088ArgfsTer28 | frameshift_variant | 5/5 | 1 | P5 | ||
PCDH19 | ENST00000420881.6 | c.3260_3261del | p.Lys1087ArgfsTer28 | frameshift_variant | 5/5 | 1 | A1 | ||
PCDH19 | ENST00000464981.1 | upstream_gene_variant | 3 |
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
Uncertain significance, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 29, 2022 | 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%). 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. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Oct 04, 2023 | Identified de novo hemizygous 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 (Nashabat et al., 2019); Frameshift variant predicted to result in protein extension as the last 14 amino acids are lost and replaced with 27 incorrect amino acids, loss-of-function variants have not been reported downstream of this position in the protein; This variant is associated with the following publications: (PMID: 31054490) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at