rs757949591
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_001184880.2(PCDH19):c.2657G>A(p.Arg886Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000186 in 1,075,807 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: not found (cov: 24)
Exomes 𝑓: 0.0000019 ( 0 hom. 1 hem. )
Consequence
PCDH19
NM_001184880.2 missense
NM_001184880.2 missense
Scores
5
5
5
Clinical Significance
Conservation
PhyloP100: 6.91
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 2 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PCDH19 | NM_001184880.2 | c.2657G>A | p.Arg886Gln | missense_variant | 4/6 | ENST00000373034.8 | |
PCDH19 | NM_001105243.2 | c.2516G>A | p.Arg839Gln | missense_variant | 3/5 | ||
PCDH19 | NM_020766.3 | c.2516G>A | p.Arg839Gln | missense_variant | 3/5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PCDH19 | ENST00000373034.8 | c.2657G>A | p.Arg886Gln | missense_variant | 4/6 | 1 | NM_001184880.2 | A1 | |
PCDH19 | ENST00000255531.8 | c.2516G>A | p.Arg839Gln | missense_variant | 3/5 | 1 | P5 | ||
PCDH19 | ENST00000420881.6 | c.2516G>A | p.Arg839Gln | missense_variant | 3/5 | 1 | A1 | ||
PCDH19 | ENST00000636150.1 | c.158G>A | p.Arg53Gln | missense_variant | 3/3 | 5 |
Frequencies
GnomAD3 genomes ? Cov.: 24
GnomAD3 genomes
?
Cov.:
24
GnomAD3 exomes AF: 0.0000111 AC: 2AN: 179913Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 65837
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GnomAD4 exome AF: 0.00000186 AC: 2AN: 1075807Hom.: 0 Cov.: 25 AF XY: 0.00000291 AC XY: 1AN XY: 343881
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GnomAD4 genome ? Cov.: 24
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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 | Jul 14, 2023 | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 886 of the PCDH19 protein (p.Arg886Gln). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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: 579743). 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
Pathogenic
D
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Uncertain
T;T;T;D
MetaSVM
Benign
T
MutationTaster
Benign
D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Benign
N;N;N;.
REVEL
Benign
Sift
Uncertain
D;D;T;.
Sift4G
Uncertain
T;D;D;.
Polyphen
1.0, 1.0
.;D;D;.
Vest4
MutPred
0.63
.;Loss of sheet (P = 0.0315);.;.;
MVP
MPC
1.5
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at