rs764980282

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 1P and 5B. PP2BP4BS2

The NM_001184880.2(PCDH19):c.559T>G(p.Phe187Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000828 in 1,207,570 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.0000088 ( 0 hom., 0 hem., cov: 24)

Exomes 𝑓: 0.0000082 ( 0 hom. 0 hem. )

Consequence

PCDH19
NM_001184880.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 5.80

Publications

0 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

PCDH19 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

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=0.3069038).

BS2

High AC in GnomAdExome4 at 9 AD,XL,Unknown gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
PCDH19	NM_001184880.2 link	c.559T>G	p.Phe187Val	missense_variant	Exon 1 of 6	ENST00000373034.8	NP_001171809.1
PCDH19	NM_001105243.2 link	c.559T>G	p.Phe187Val	missense_variant	Exon 1 of 5		NP_001098713.1
PCDH19	NM_020766.3 link	c.559T>G	p.Phe187Val	missense_variant	Exon 1 of 5		NP_065817.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
PCDH19	ENST00000373034.8 link	c.559T>G	p.Phe187Val	missense_variant	Exon 1 of 6	1	NM_001184880.2	ENSP00000362125.4
PCDH19	ENST00000255531.8 link	c.559T>G	p.Phe187Val	missense_variant	Exon 1 of 5	1		ENSP00000255531.7
PCDH19	ENST00000420881.6 link	c.559T>G	p.Phe187Val	missense_variant	Exon 1 of 5	1		ENSP00000400327.2

Frequencies

GnomAD3 genomes

AF:

0.00000885

AC:

AN:

113020

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000922

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000393

AC:

AN:

178246

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000219

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:

0.000226

GnomAD4 exome

AF:

0.00000822

AC:

AN:

1094550

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

361716

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26401

American (AMR)

AF:

0.000227

AC:

AN:

35203

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19384

East Asian (EAS)

AF:

0.00

AC:

AN:

30205

South Asian (SAS)

AF:

0.00

AC:

AN:

54147

European-Finnish (FIN)

AF:

0.00

AC:

AN:

36893

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4136

European-Non Finnish (NFE)

AF:

0.00000119

AC:

AN:

842110

Other (OTH)

AF:

0.00

AC:

AN:

46071

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.00000885

AC:

AN:

113020

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

35196

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

31145

American (AMR)

AF:

0.0000922

AC:

AN:

10848

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2660

East Asian (EAS)

AF:

0.00

AC:

AN:

3553

South Asian (SAS)

AF:

0.00

AC:

AN:

2769

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6252

Middle Eastern (MID)

AF:

0.00

AC:

AN:

240

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53341

Other (OTH)

AF:

0.00

AC:

AN:

1531

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000248

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Jan 23, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.559T>G (p.F187V) alteration is located in exon 1 (coding exon 1) of the PCDH19 gene. This alteration results from a T to G substitution at nucleotide position 559, causing the phenylalanine (F) at amino acid position 187 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Sep 05, 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

May 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces phenylalanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 187 of the PCDH19 protein (p.Phe187Val). This variant is present in population databases (rs764980282, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of PCDH19-related conditions (Invitae). ClinVar contains an entry for this variant (Variation ID: 193197). Advanced 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 at Invitae 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

Pathogenic

0.69

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.32

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.22

.;T;.

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.90

D;D;D

M_CAP

Uncertain

0.27

MetaRNN

Benign

0.31

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.80

N;N;N

PhyloP100

5.8

PrimateAI

Uncertain

0.75

PROVEAN

Pathogenic

-4.6

D;D;D

REVEL

Benign

0.19

Sift

Uncertain

0.0020

D;D;D

Sift4G

Uncertain

0.022

D;D;D

Polyphen

0.27, 0.36

.;B;B

Vest4

0.62

MutPred

0.34

Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);

MVP

0.58

MPC

2.1

ClinPred

0.20

GERP RS

5.7

Varity_R

0.95

gMVP

0.66

Mutation Taster

=35/65

disease causing

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over