chrX-100408039-A-C
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Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM1BP4
The NM_001184880.2(PCDH19):āc.559T>Gā(p.Phe187Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000828 in 1,207,570 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ā ).
Frequency
Genomes: š 0.0000088 ( 0 hom., 0 hem., cov: 24)
Exomes š: 0.0000082 ( 0 hom. 0 hem. )
Consequence
PCDH19
NM_001184880.2 missense
NM_001184880.2 missense
Scores
2
7
7
Clinical Significance
Conservation
PhyloP100: 5.80
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 Uncertain_significance. Variant got 1 ACMG points.
PM1
In a domain Cadherin 2 (size 108) in uniprot entity PCD19_HUMAN there are 37 pathogenic changes around while only 2 benign (95%) in NM_001184880.2
BP4
Computational evidence support a benign effect (MetaRNN=0.3069038).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PCDH19 | NM_001184880.2 | c.559T>G | p.Phe187Val | missense_variant | 1/6 | ENST00000373034.8 | |
PCDH19 | NM_001105243.2 | c.559T>G | p.Phe187Val | missense_variant | 1/5 | ||
PCDH19 | NM_020766.3 | c.559T>G | p.Phe187Val | missense_variant | 1/5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PCDH19 | ENST00000373034.8 | c.559T>G | p.Phe187Val | missense_variant | 1/6 | 1 | NM_001184880.2 | A1 | |
PCDH19 | ENST00000255531.8 | c.559T>G | p.Phe187Val | missense_variant | 1/5 | 1 | P5 | ||
PCDH19 | ENST00000420881.6 | c.559T>G | p.Phe187Val | missense_variant | 1/5 | 1 | A1 |
Frequencies
GnomAD3 genomes AF: 0.00000885 AC: 1AN: 113020Hom.: 0 Cov.: 24 AF XY: 0.00 AC XY: 0AN XY: 35196
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GnomAD3 exomes AF: 0.0000393 AC: 7AN: 178246Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 65556
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GnomAD4 exome AF: 0.00000822 AC: 9AN: 1094550Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 361716
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GnomAD4 genome AF: 0.00000885 AC: 1AN: 113020Hom.: 0 Cov.: 24 AF XY: 0.00 AC XY: 0AN XY: 35196
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Sep 05, 2014 | - - |
Developmental and epileptic encephalopathy, 9 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 27, 2023 | This sequence change replaces phenylalanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 187 of the PCDH19 protein (p.Phe187Val). This variant is present in population databases (rs764980282, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of PCDH19-related conditions (Invitae). ClinVar contains an entry for this variant (Variation ID: 193197). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on 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. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D
M_CAP
Uncertain
D
MetaRNN
Benign
T;T;T
MetaSVM
Benign
T
MutationAssessor
Benign
N;N;N
MutationTaster
Benign
D;D;D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D;D
REVEL
Benign
Sift
Uncertain
D;D;D
Sift4G
Uncertain
D;D;D
Polyphen
0.27, 0.36
.;B;B
Vest4
MutPred
Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);
MVP
MPC
2.1
ClinPred
T
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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