chrX-100407912-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001184880.2(PCDH19):​c.686C>T​(p.Thr229Ile) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 24)
Exomes 𝑓: 0.0000018 ( 0 hom. 2 hem. )
Failed GnomAD Quality Control

Consequence

PCDH19
NM_001184880.2 missense

Scores

3
14

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 4.72
Variant links:
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 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.22448483).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
PCDH19NM_001184880.2 linkuse as main transcriptc.686C>T p.Thr229Ile missense_variant 1/6 ENST00000373034.8 NP_001171809.1 Q8TAB3-1
PCDH19NM_001105243.2 linkuse as main transcriptc.686C>T p.Thr229Ile missense_variant 1/5 NP_001098713.1 Q8TAB3-2B3KU71
PCDH19NM_020766.3 linkuse as main transcriptc.686C>T p.Thr229Ile missense_variant 1/5 NP_065817.2 Q8TAB3-3B3KU71

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
PCDH19ENST00000373034.8 linkuse as main transcriptc.686C>T p.Thr229Ile missense_variant 1/61 NM_001184880.2 ENSP00000362125.4 Q8TAB3-1
PCDH19ENST00000255531.8 linkuse as main transcriptc.686C>T p.Thr229Ile missense_variant 1/51 ENSP00000255531.7 Q8TAB3-2
PCDH19ENST00000420881.6 linkuse as main transcriptc.686C>T p.Thr229Ile missense_variant 1/51 ENSP00000400327.2 Q8TAB3-3

Frequencies

GnomAD3 genomes
Cov.:
24
GnomAD3 exomes
AF:
0.00000553
AC:
1
AN:
180923
Hom.:
0
AF XY:
0.0000149
AC XY:
1
AN XY:
66897
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000738
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
Data not reliable, filtered out with message: AS_VQSR
AF:
0.00000182
AC:
2
AN:
1097613
Hom.:
0
Cov.:
33
AF XY:
0.00000551
AC XY:
2
AN XY:
363071
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000331
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000119
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
24

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Developmental and epileptic encephalopathy, 9 Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoMay 30, 2014- -
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 20, 2023In 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. 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. ClinVar contains an entry for this variant (Variation ID: 159560). This variant has not been reported in the literature in individuals affected with PCDH19-related conditions. This variant is present in population databases (rs587784298, gnomAD 0.008%). This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 229 of the PCDH19 protein (p.Thr229Ile). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.11
BayesDel_addAF
Benign
-0.45
T
BayesDel_noAF
Benign
-0.70
CADD
Benign
19
DANN
Benign
0.80
DEOGEN2
Benign
0.038
.;T;.
FATHMM_MKL
Uncertain
0.86
D
LIST_S2
Benign
0.83
T;D;T
M_CAP
Uncertain
0.13
D
MetaRNN
Benign
0.22
T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
1.3
L;L;L
PrimateAI
Uncertain
0.52
T
PROVEAN
Benign
0.78
N;N;N
REVEL
Benign
0.046
Sift
Benign
0.95
T;T;T
Sift4G
Benign
1.0
T;T;T
Polyphen
0.0010
.;B;B
Vest4
0.17
MutPred
0.43
Loss of phosphorylation at T229 (P = 0.03);Loss of phosphorylation at T229 (P = 0.03);Loss of phosphorylation at T229 (P = 0.03);
MVP
0.55
MPC
1.3
ClinPred
0.13
T
GERP RS
5.0
Varity_R
0.45
gMVP
0.39

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs587784298; hg19: chrX-99662910; API