rs796052790
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM1BP4_ModerateBS2
The NM_001184880.2(PCDH19):āc.224A>Gā(p.Asn75Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000497 in 1,207,697 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ā ).
Frequency
Consequence
NM_001184880.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PCDH19 | NM_001184880.2 | c.224A>G | p.Asn75Ser | missense_variant | 1/6 | ENST00000373034.8 | |
PCDH19 | NM_001105243.2 | c.224A>G | p.Asn75Ser | missense_variant | 1/5 | ||
PCDH19 | NM_020766.3 | c.224A>G | p.Asn75Ser | missense_variant | 1/5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PCDH19 | ENST00000373034.8 | c.224A>G | p.Asn75Ser | missense_variant | 1/6 | 1 | NM_001184880.2 | A1 | |
PCDH19 | ENST00000255531.8 | c.224A>G | p.Asn75Ser | missense_variant | 1/5 | 1 | P5 | ||
PCDH19 | ENST00000420881.6 | c.224A>G | p.Asn75Ser | missense_variant | 1/5 | 1 | A1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000360 AC: 4AN: 110993Hom.: 0 Cov.: 24 AF XY: 0.0000602 AC XY: 2AN XY: 33213
GnomAD3 exomes AF: 0.00000556 AC: 1AN: 179728Hom.: 0 AF XY: 0.0000151 AC XY: 1AN XY: 66020
GnomAD4 exome AF: 0.00000182 AC: 2AN: 1096704Hom.: 0 Cov.: 32 AF XY: 0.00000276 AC XY: 1AN XY: 362332
GnomAD4 genome ? AF: 0.0000360 AC: 4AN: 110993Hom.: 0 Cov.: 24 AF XY: 0.0000602 AC XY: 2AN XY: 33213
ClinVar
Submissions by phenotype
Developmental and epileptic encephalopathy, 9 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 05, 2023 | This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 75 of the PCDH19 protein (p.Asn75Ser). This variant is present in population databases (rs796052790, gnomAD 0.005%). This variant has not been reported in the literature in individuals affected with PCDH19-related conditions. ClinVar contains an entry for this variant (Variation ID: 206292). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PCDH19 protein function. 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. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Jan 09, 2020 | DNA sequence analysis of the PCDH19 gene demonstrated a sequence change, c.224A>G, in exon 1 that results in an amino acid change, p.Asn75Ser. This sequence change does not appear to have been previously described in patients with PCDH19-related disorders. This particular sequence change has been described in the gnomAD database in two individuals in the hemizygous state which corresponds to a population frequency of 0.00099% (dbSNP rs796052790). The p.Asn75Ser change affects a moderately conserved amino acid residue located in a domain of the PCDH19 protein that is known to be functional. The p.Asn75Ser substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Asn75Ser change remains unknown at this time. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Aug 16, 2019 | The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge - |
Neurodevelopmental disorder with epilepsy Benign:1
Benign, no assertion criteria provided | research | Neurogenetics Research Program, University of Adelaide | Dec 20, 2019 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at