rs3764758

Positions:

chrX-100296786-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The ENST00000373034.8(PCDH19):c.2938C>T(p.Arg980Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00131 in 1,209,314 control chromosomes in the GnomAD database, including 21 homozygotes. There are 488 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R980H) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0020 ( 3 hom., 79 hem., cov: 22)

Exomes 𝑓: 0.0012 ( 18 hom. 409 hem. )

Consequence

PCDH19
ENST00000373034.8 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 4.52

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.010465592).

BP6

Variant X-100296786-G-A is Benign according to our data. Variant chrX-100296786-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 138590.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-100296786-G-A is described in Lovd as [Likely_benign]. Variant chrX-100296786-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0501 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
PCDH19	NM_001184880.2 linkuse as main transcript	c.2938C>T	p.Arg980Cys	missense_variant	6/6	ENST00000373034.8	NP_001171809.1
PCDH19	NM_001105243.2 linkuse as main transcript	c.2797C>T	p.Arg933Cys	missense_variant	5/5		NP_001098713.1
PCDH19	NM_020766.3 linkuse as main transcript	c.2794C>T	p.Arg932Cys	missense_variant	5/5		NP_065817.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCDH19	ENST00000373034.8 linkuse as main transcript	c.2938C>T	p.Arg980Cys	missense_variant	6/6	1	NM_001184880.2	ENSP00000362125	A1	Q8TAB3-1
PCDH19	ENST00000255531.8 linkuse as main transcript	c.2797C>T	p.Arg933Cys	missense_variant	5/5	1		ENSP00000255531	P5	Q8TAB3-2
PCDH19	ENST00000420881.6 linkuse as main transcript	c.2794C>T	p.Arg932Cys	missense_variant	5/5	1		ENSP00000400327	A1	Q8TAB3-3

Frequencies

GnomAD3 genomes

AF:

0.00204

AC:

228

AN:

111790

Hom.:

Cov.:

AF XY:

0.00233

AC XY:

AN XY:

33946

show subpopulations

Gnomad AFR

AF:

0.000488

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000189

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0563

Gnomad SAS

AF:

0.00270

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000752

Gnomad OTH

AF:

0.000665

GnomAD3 exomes

AF:

0.00479

AC:

870

AN:

181478

Hom.:

AF XY:

0.00405

AC XY:

273

AN XY:

67446

show subpopulations

Gnomad AFR exome

AF:

0.000645

Gnomad AMR exome

AF:

0.000110

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0609

Gnomad SAS exome

AF:

0.00136

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000246

Gnomad OTH exome

AF:

0.00135

GnomAD4 exome

AF:

0.00124

AC:

1359

AN:

1097470

Hom.:

Cov.:

AF XY:

0.00113

AC XY:

409

AN XY:

362840

show subpopulations

Gnomad4 AFR exome

AF:

0.000303

Gnomad4 AMR exome

AF:

0.000114

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0377

Gnomad4 SAS exome

AF:

0.00139

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000357

Gnomad4 OTH exome

AF:

0.00224

GnomAD4 genome

AF:

0.00204

AC:

228

AN:

111844

Hom.:

Cov.:

AF XY:

0.00232

AC XY:

AN XY:

34010

show subpopulations

Gnomad4 AFR

AF:

0.000487

Gnomad4 AMR

AF:

0.000188

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.0565

Gnomad4 SAS

AF:

0.00270

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000752

Gnomad4 OTH

AF:

0.000657

Alfa

AF:

0.00200

Hom.:

Bravo

AF:

0.00244

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000346

AC:

ESP6500AA

AF:

0.000838

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00452

AC:

547

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 17, 2013	This 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. -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Mar 27, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 27, 2014	- -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 18, 2016

This 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. -

Developmental and epileptic encephalopathy, 9

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.28

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.32

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.061

.;T;.

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.90

D;D;D

MetaRNN

Benign

0.010

T;T;T

MetaSVM

Benign

-0.66

MutationAssessor

Benign

1.9

.;M;.

MutationTaster

Benign

1.2e-9

P;P;P

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-2.0

N;N;N

REVEL

Benign

0.15

Sift

Benign

0.064

T;T;T

Sift4G

Uncertain

0.046

D;D;D

Polyphen

0.0020, 1.0

.;B;D

Vest4

0.15

MVP

0.67

MPC

0.69

ClinPred

0.016

GERP RS

4.1

Varity_R

0.14

gMVP

0.52

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over