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GeneBe

rs61744561

chrX-100402671-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_001184880.2(PCDH19):c.2469G>A(p.Leu823=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00147 in 1,210,055 control chromosomes in the GnomAD database, including 19 homozygotes. There are 445 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. L823L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0075 ( 10 hom., 218 hem., cov: 23)
Exomes 𝑓: 0.00086 ( 9 hom. 227 hem. )

Consequence

PCDH19
NM_001184880.2 synonymous

Scores

2

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 1.66
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 Benign. Variant got -19 ACMG points.

BP4
?
    BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (BayesDel_noAF=-0.4).
BP6
?
    BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant X-100402671-C-T is Benign according to our data. Variant chrX-100402671-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 93673.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP7
?
    BP7 - A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved
Synonymous conserved (PhyloP=1.66 with no splicing effect.
BS1
?
    BS1 - Allele frequency is greater than expected for disorder
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00749 (839/112034) while in subpopulation AFR AF= 0.026 (802/30843). AF 95% confidence interval is 0.0245. There are 10 homozygotes in gnomad4. There are 218 alleles in male gnomad4 subpopulation. This position pass quality control queck.
BS2
?
    BS2 - Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age
High Homozygotes in GnomAd at 10 XL gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
PCDH19NM_001184880.2 linkuse as main transcriptc.2469G>A p.Leu823= synonymous_variant 3/6 ENST00000373034.8
PCDH19NM_001105243.2 linkuse as main transcriptc.2328G>A p.Leu776= synonymous_variant 2/5
PCDH19NM_020766.3 linkuse as main transcriptc.2328G>A p.Leu776= synonymous_variant 2/5

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
PCDH19ENST00000373034.8 linkuse as main transcriptc.2469G>A p.Leu823= synonymous_variant 3/61 NM_001184880.2 A1Q8TAB3-1
PCDH19ENST00000255531.8 linkuse as main transcriptc.2328G>A p.Leu776= synonymous_variant 2/51 P5Q8TAB3-2
PCDH19ENST00000420881.6 linkuse as main transcriptc.2328G>A p.Leu776= synonymous_variant 2/51 A1Q8TAB3-3
PCDH19ENST00000636150.1 linkuse as main transcriptc.66-96G>A intron_variant 5

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.00747
AC:
836
AN:
111985
Hom.:
10
Cov.:
23
AF XY:
0.00632
AC XY:
216
AN XY:
34161
show subpopulations
Gnomad AFR
AF:
0.0260
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00245
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:
0.0000940
Gnomad OTH
AF:
0.00397
GnomAD3 exomes
AF:
0.00218
AC:
396
AN:
181280
Hom.:
1
AF XY:
0.00129
AC XY:
87
AN XY:
67232
show subpopulations
Gnomad AFR exome
AF:
0.0281
Gnomad AMR exome
AF:
0.00139
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000526
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000615
Gnomad OTH exome
AF:
0.00113
GnomAD4 exome
AF:
0.000859
AC:
943
AN:
1098021
Hom.:
9
Cov.:
31
AF XY:
0.000625
AC XY:
227
AN XY:
363395
show subpopulations
Gnomad4 AFR exome
AF:
0.0293
Gnomad4 AMR exome
AF:
0.00148
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000924
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000273
Gnomad4 OTH exome
AF:
0.00189
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.00749
AC:
839
AN:
112034
Hom.:
10
Cov.:
23
AF XY:
0.00637
AC XY:
218
AN XY:
34220
show subpopulations
Gnomad4 AFR
AF:
0.0260
Gnomad4 AMR
AF:
0.00244
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000940
Gnomad4 OTH
AF:
0.00392
Alfa
AF:
0.00330
Hom.:
8
Bravo
AF:
0.00853
EpiCase
AF:
0.00
EpiControl
AF:
0.0000594

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:3
Benign, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Feb 15, 2013- -
Benign, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoFeb 08, 2013- -
Benign, criteria provided, single submitterclinical testingGeneDxJan 08, 2013This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Developmental and epileptic encephalopathy, 9 Benign:2
Likely benign, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsMay 17, 2022- -
Benign, criteria provided, single submitterclinical testingInvitaeJan 30, 2024- -
Inborn genetic diseases Benign:1
Benign, criteria provided, single submitterclinical testingAmbry GeneticsMar 21, 2016This alteration is classified as 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. -
not provided Benign:1
Benign, criteria provided, single submitterclinical testingAthena DiagnosticsMay 01, 2018- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.40
Cadd
Benign
8.1
Dann
Benign
0.72

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: rs61744561; hg19: chrX-99657669; API