rs201671718
Positions:
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM1BP6BS2
The NM_001184880.2(PCDH19):āc.1330A>Gā(p.Thr444Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000152 in 1,210,289 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 63 hemizygotes in GnomAD. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: š 0.00013 ( 0 hom., 4 hem., cov: 24)
Exomes š: 0.00015 ( 0 hom. 59 hem. )
Consequence
PCDH19
NM_001184880.2 missense
NM_001184880.2 missense
Scores
6
10
Clinical Significance
Conservation
PhyloP100: 3.36
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 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 8 uncertain in NM_001184880.2
BP6
?
Variant X-100407268-T-C is Benign according to our data. Variant chrX-100407268-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 206296.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=3}.
BS2
?
High Hemizygotes in GnomAd4 at 4 XL gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PCDH19 | NM_001184880.2 | c.1330A>G | p.Thr444Ala | missense_variant | 1/6 | ENST00000373034.8 | |
PCDH19 | NM_001105243.2 | c.1330A>G | p.Thr444Ala | missense_variant | 1/5 | ||
PCDH19 | NM_020766.3 | c.1330A>G | p.Thr444Ala | missense_variant | 1/5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PCDH19 | ENST00000373034.8 | c.1330A>G | p.Thr444Ala | missense_variant | 1/6 | 1 | NM_001184880.2 | A1 | |
PCDH19 | ENST00000255531.8 | c.1330A>G | p.Thr444Ala | missense_variant | 1/5 | 1 | P5 | ||
PCDH19 | ENST00000420881.6 | c.1330A>G | p.Thr444Ala | missense_variant | 1/5 | 1 | A1 |
Frequencies
GnomAD3 genomes ? AF: 0.000134 AC: 15AN: 112069Hom.: 0 Cov.: 24 AF XY: 0.000117 AC XY: 4AN XY: 34283
GnomAD3 genomes
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GnomAD3 exomes AF: 0.000132 AC: 24AN: 181876Hom.: 0 AF XY: 0.000118 AC XY: 8AN XY: 67696
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GnomAD4 exome AF: 0.000154 AC: 169AN: 1098220Hom.: 0 Cov.: 33 AF XY: 0.000162 AC XY: 59AN XY: 363574
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GnomAD4 genome ? AF: 0.000134 AC: 15AN: 112069Hom.: 0 Cov.: 24 AF XY: 0.000117 AC XY: 4AN XY: 34283
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:5
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:1Benign:1
Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The PCDH19 p.Thr444Ala variant was not identified in the literature nor was it identified in Cosmic or LOVD 3.0. The variant was identified in dbSNP (ID: rs201671718) and in ClinVar (classified as likely benign by GeneDx and Uncertain significance by Genetic Services Laboratory, University of Chicago). The variant was also identified in control databases in 26 of 203692 chromosomes (8 hemizygous) at a frequency of 0.000128 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European (non-Finnish) in 25 of 92285 chromosomes (freq: 0.0002709) and Other in 1 of 5270 chromosome (freq: 0.0001898), but not in the African, Latino, Ashkenazi Jewish, East Asian, European (Finnish), and South Asian populations. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. The p.Thr444 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Jun 25, 2020 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Dec 21, 2015 | - - |
Inborn genetic diseases Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 09, 2018 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
sporadic NAFE Benign:1
Likely benign, no assertion criteria provided | research | Neurogenetics Research Program, University of Adelaide | Dec 20, 2019 | - - |
Neurodevelopmental disorder with epilepsy Benign:1
Likely benign, no assertion criteria provided | research | Neurogenetics Research Program, University of Adelaide | Dec 20, 2019 | - - |
Developmental and epileptic encephalopathy, 9 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Nov 27, 2023 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T;T;T
M_CAP
Uncertain
D
MetaRNN
Uncertain
D;D;D
MetaSVM
Benign
T
MutationAssessor
Benign
N;N;N
MutationTaster
Benign
D;D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N;N
REVEL
Uncertain
Sift
Benign
T;T;T
Sift4G
Benign
T;T;T
Polyphen
1.0, 0.98
.;D;D
Vest4
MVP
MPC
1.4
ClinPred
T
GERP RS
Varity_R
gMVP
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