chrX-100407808-C-G

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong

The NM_001184880.2(PCDH19):​c.790G>C​(p.Asp264His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D264Y) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 24)

Consequence

PCDH19
NM_001184880.2 missense

Scores

11
5
1

Clinical Significance

Likely pathogenic criteria provided, multiple submitters, no conflicts P:2

Conservation

PhyloP100: 7.91
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 Pathogenic. Variant got 16 ACMG points.

PM1
In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 7 uncertain in NM_001184880.2
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.991
PP5
Variant X-100407808-C-G is Pathogenic according to our data. Variant chrX-100407808-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 839943.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-100407808-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PCDH19NM_001184880.2 linkc.790G>C p.Asp264His missense_variant Exon 1 of 6 ENST00000373034.8 NP_001171809.1 Q8TAB3-1
PCDH19NM_001105243.2 linkc.790G>C p.Asp264His missense_variant Exon 1 of 5 NP_001098713.1 Q8TAB3-2B3KU71
PCDH19NM_020766.3 linkc.790G>C p.Asp264His missense_variant Exon 1 of 5 NP_065817.2 Q8TAB3-3B3KU71

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PCDH19ENST00000373034.8 linkc.790G>C p.Asp264His missense_variant Exon 1 of 6 1 NM_001184880.2 ENSP00000362125.4 Q8TAB3-1
PCDH19ENST00000255531.8 linkc.790G>C p.Asp264His missense_variant Exon 1 of 5 1 ENSP00000255531.7 Q8TAB3-2
PCDH19ENST00000420881.6 linkc.790G>C p.Asp264His missense_variant Exon 1 of 5 1 ENSP00000400327.2 Q8TAB3-3

Frequencies

GnomAD3 genomes
Cov.:
24
GnomAD4 exome
Cov.:
33
GnomAD4 genome
Cov.:
24

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Intellectual disability Pathogenic:1
Apr 20, 2020
Diagnostic Laboratory, Strasbourg University Hospital
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Developmental and epileptic encephalopathy, 9 Pathogenic:1
Aug 28, 2021
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.52
D
BayesDel_noAF
Pathogenic
0.51
CADD
Pathogenic
30
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.52
.;D;.
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.96
D;D;D
M_CAP
Pathogenic
0.87
D
MetaRNN
Pathogenic
0.99
D;D;D
MetaSVM
Pathogenic
0.99
D
MutationAssessor
Pathogenic
4.4
H;H;H
PrimateAI
Pathogenic
0.81
D
PROVEAN
Pathogenic
-6.5
D;D;D
REVEL
Pathogenic
0.82
Sift
Uncertain
0.0010
D;D;D
Sift4G
Uncertain
0.0020
D;D;D
Polyphen
1.0
.;D;D
Vest4
0.97
MutPred
0.92
Loss of disorder (P = 0.1155);Loss of disorder (P = 0.1155);Loss of disorder (P = 0.1155);
MVP
0.99
MPC
2.6
ClinPred
1.0
D
GERP RS
6.0
Varity_R
0.98
gMVP
0.98

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: rs587784300; hg19: chrX-99662806; API