rs200142964
Positions:
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM1BP4BS2
The NM_001184880.2(PCDH19):c.650C>A(p.Pro217Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000182 in 1,209,185 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 (★).
Frequency
Genomes: 𝑓 0.000018 ( 0 hom., 0 hem., cov: 24)
Exomes 𝑓: 0.000018 ( 0 hom. 3 hem. )
Consequence
PCDH19
NM_001184880.2 missense
NM_001184880.2 missense
Scores
1
5
10
Clinical Significance
Conservation
PhyloP100: 8.13
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 Likely_benign. Variant got -3 ACMG points.
PM1
?
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 7 uncertain in NM_001184880.2
BP4
?
Computational evidence support a benign effect (MetaRNN=0.29055735).
BS2
?
High Hemizygotes in GnomAdExome4 at 3 XL gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PCDH19 | NM_001184880.2 | c.650C>A | p.Pro217Gln | missense_variant | 1/6 | ENST00000373034.8 | |
PCDH19 | NM_001105243.2 | c.650C>A | p.Pro217Gln | missense_variant | 1/5 | ||
PCDH19 | NM_020766.3 | c.650C>A | p.Pro217Gln | missense_variant | 1/5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PCDH19 | ENST00000373034.8 | c.650C>A | p.Pro217Gln | missense_variant | 1/6 | 1 | NM_001184880.2 | A1 | |
PCDH19 | ENST00000255531.8 | c.650C>A | p.Pro217Gln | missense_variant | 1/5 | 1 | P5 | ||
PCDH19 | ENST00000420881.6 | c.650C>A | p.Pro217Gln | missense_variant | 1/5 | 1 | A1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000177 AC: 2AN: 113308Hom.: 0 Cov.: 24 AF XY: 0.00 AC XY: 0AN XY: 35446
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GnomAD3 exomes AF: 0.0000446 AC: 8AN: 179262Hom.: 0 AF XY: 0.0000152 AC XY: 1AN XY: 65898
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GnomAD4 exome AF: 0.0000183 AC: 20AN: 1095877Hom.: 0 Cov.: 33 AF XY: 0.00000829 AC XY: 3AN XY: 362045
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Developmental and epileptic encephalopathy, 9 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 17, 2023 | This sequence change replaces proline, which is neutral and non-polar, with glutamine, which is neutral and polar, at codon 217 of the PCDH19 protein (p.Pro217Gln). This variant is present in population databases (rs200142964, gnomAD 0.07%). 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: 465308). 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
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Benign
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D
M_CAP
Uncertain
D
MetaRNN
Benign
T;T;T
MetaSVM
Benign
T
MutationAssessor
Benign
L;L;L
MutationTaster
Benign
D;D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D;D
REVEL
Uncertain
Sift
Benign
T;T;T
Sift4G
Benign
T;T;T
Polyphen
1.0, 0.99
.;D;D
Vest4
MutPred
Loss of methylation at R218 (P = 0.0666);Loss of methylation at R218 (P = 0.0666);Loss of methylation at R218 (P = 0.0666);
MVP
MPC
2.3
ClinPred
T
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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