chrX-100408053-C-G

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 3P and 6B. PM1PP2BP4BP6BS2

The NM_001184880.2(PCDH19):​c.545G>C​(p.Gly182Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0000796 in 113,113 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G182R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000080 ( 0 hom., 4 hem., cov: 24)
Exomes 𝑓: 0.0000055 ( 0 hom. 4 hem. )
Failed GnomAD Quality Control

Consequence

PCDH19
NM_001184880.2 missense

Scores

7
10

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 4.96

Publications

1 publications found
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]
PCDH19 Gene-Disease associations (from GenCC):
  • developmental and epileptic encephalopathy, 9
    Inheritance: XL, Unknown Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics
  • X-linked complex neurodevelopmental disorder
    Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
  • Dravet syndrome
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

PM1
In a domain Cadherin 2 (size 108) in uniprot entity PCD19_HUMAN there are 34 pathogenic changes around while only 2 benign (94%) in NM_001184880.2
PP2
Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 107 curated pathogenic missense variants (we use a threshold of 10). The gene has 20 curated benign missense variants. Gene score misZ: 2.5929 (below the threshold of 3.09). Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to Dravet syndrome, developmental and epileptic encephalopathy, 9, X-linked complex neurodevelopmental disorder.
BP4
Computational evidence support a benign effect (MetaRNN=0.30897903).
BP6
Variant X-100408053-C-G is Benign according to our data. Variant chrX-100408053-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 167421.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].
BS2
High AC in GnomAd4 at 9 AD,XL,Unknown gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PCDH19NM_001184880.2 linkc.545G>C p.Gly182Ala missense_variant Exon 1 of 6 ENST00000373034.8 NP_001171809.1 Q8TAB3-1
PCDH19NM_001105243.2 linkc.545G>C p.Gly182Ala missense_variant Exon 1 of 5 NP_001098713.1 Q8TAB3-2B3KU71
PCDH19NM_020766.3 linkc.545G>C p.Gly182Ala 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.545G>C p.Gly182Ala missense_variant Exon 1 of 6 1 NM_001184880.2 ENSP00000362125.4 Q8TAB3-1
PCDH19ENST00000255531.8 linkc.545G>C p.Gly182Ala missense_variant Exon 1 of 5 1 ENSP00000255531.7 Q8TAB3-2
PCDH19ENST00000420881.6 linkc.545G>C p.Gly182Ala missense_variant Exon 1 of 5 1 ENSP00000400327.2 Q8TAB3-3

Frequencies

GnomAD3 genomes
AF:
0.0000796
AC:
9
AN:
113113
Hom.:
0
Cov.:
24
show subpopulations
Gnomad AFR
AF:
0.000257
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000187
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.0000112
AC:
2
AN:
178452
AF XY:
0.0000305
show subpopulations
Gnomad AFR exome
AF:
0.000162
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS 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:
0.00000548
AC:
6
AN:
1094944
Hom.:
0
Cov.:
33
AF XY:
0.0000111
AC XY:
4
AN XY:
361904
show subpopulations
African (AFR)
AF:
0.000114
AC:
3
AN:
26402
American (AMR)
AF:
0.00
AC:
0
AN:
35201
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
19384
East Asian (EAS)
AF:
0.00
AC:
0
AN:
30205
South Asian (SAS)
AF:
0.00
AC:
0
AN:
54149
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
37277
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
4137
European-Non Finnish (NFE)
AF:
0.00000356
AC:
3
AN:
842116
Other (OTH)
AF:
0.00
AC:
0
AN:
46073
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.525
Heterozygous variant carriers
0
1
1
2
2
3
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.0000796
AC:
9
AN:
113113
Hom.:
0
Cov.:
24
AF XY:
0.000113
AC XY:
4
AN XY:
35269
show subpopulations
African (AFR)
AF:
0.000257
AC:
8
AN:
31159
American (AMR)
AF:
0.00
AC:
0
AN:
10852
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
2660
East Asian (EAS)
AF:
0.00
AC:
0
AN:
3559
South Asian (SAS)
AF:
0.00
AC:
0
AN:
2783
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
6265
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
240
European-Non Finnish (NFE)
AF:
0.0000187
AC:
1
AN:
53381
Other (OTH)
AF:
0.00
AC:
0
AN:
1529
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.515
Heterozygous variant carriers
0
1
1
2
2
3
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Genome Hom
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.0000712
Hom.:
0
Bravo
AF:
0.0000453

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:1Benign:1
May 01, 2019
GeneDx
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Apr 04, 2014
Eurofins Ntd Llc (ga)
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Developmental and epileptic encephalopathy, 9 Uncertain:1
Nov 19, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 182 of the PCDH19 protein (p.Gly182Ala). This variant is present in population databases (rs727504067, gnomAD 0.02%). 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: 167421). Invitae Evidence 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 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.42
BayesDel_addAF
Benign
-0.22
T
BayesDel_noAF
Benign
-0.36
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Benign
0.060
.;T;.
FATHMM_MKL
Uncertain
0.97
D
LIST_S2
Uncertain
0.93
D;D;D
M_CAP
Uncertain
0.13
D
MetaRNN
Benign
0.31
T;T;T
MetaSVM
Benign
-0.83
T
MutationAssessor
Benign
-0.85
N;N;N
PhyloP100
5.0
PrimateAI
Uncertain
0.78
T
PROVEAN
Benign
-1.8
N;N;N
REVEL
Benign
0.22
Sift
Benign
0.041
D;D;D
Sift4G
Uncertain
0.027
D;D;D
Polyphen
1.0
.;D;D
Vest4
0.59
MutPred
0.26
Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);
MVP
0.79
MPC
2.5
ClinPred
0.38
T
GERP RS
5.7
Varity_R
0.68
gMVP
0.73
Mutation Taster
=71/29
polymorphism

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

Other links and lift over

dbSNP: rs727504067; hg19: chrX-99663051; API