X-100296309-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001184880.2(PCDH19):c.3415G>A(p.Gly1139Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000111 in 1,209,298 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 91 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 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. G1139D) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000027 ( 0 hom., 2 hem., cov: 22)

Exomes 𝑓: 0.00012 ( 0 hom. 89 hem. )

Consequence

PCDH19
NM_001184880.2 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 2.36

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=0.0063087046).

BP6

Variant X-100296309-C-T is Benign according to our data. Variant chrX-100296309-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 206287.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-100296309-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0000268 (3/111959) while in subpopulation SAS AF= 0.00114 (3/2640). AF 95% confidence interval is 0.000309. There are 0 homozygotes in gnomad4. There are 2 alleles in male gnomad4 subpopulation. Median coverage is 22. This position pass quality control queck.

BS2

High Hemizygotes in GnomAd at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
PCDH19	NM_001184880.2 linkuse as main transcript	c.3415G>A	p.Gly1139Ser	missense_variant	6/6	ENST00000373034.8
PCDH19	NM_001105243.2 linkuse as main transcript	c.3274G>A	p.Gly1092Ser	missense_variant	5/5
PCDH19	NM_020766.3 linkuse as main transcript	c.3271G>A	p.Gly1091Ser	missense_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCDH19	ENST00000373034.8 linkuse as main transcript	c.3415G>A	p.Gly1139Ser	missense_variant	6/6	1	NM_001184880.2	A1	Q8TAB3-1
PCDH19	ENST00000255531.8 linkuse as main transcript	c.3274G>A	p.Gly1092Ser	missense_variant	5/5	1		P5	Q8TAB3-2
PCDH19	ENST00000420881.6 linkuse as main transcript	c.3271G>A	p.Gly1091Ser	missense_variant	5/5	1		A1	Q8TAB3-3
PCDH19	ENST00000464981.1 linkuse as main transcript			upstream_gene_variant		3

Frequencies

GnomAD3 genomes

AF:

0.0000268

AC:

AN:

111906

Hom.:

Cov.:

AF XY:

0.0000587

AC XY:

AN XY:

34078

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00113

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000275

AC:

AN:

181615

Hom.:

AF XY:

0.000518

AC XY:

AN XY:

67539

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00262

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000119

AC:

131

AN:

1097339

Hom.:

Cov.:

AF XY:

0.000245

AC XY:

AN XY:

362715

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00236

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000434

GnomAD4 genome

AF:

0.0000268

AC:

AN:

111959

Hom.:

Cov.:

AF XY:

0.0000586

AC XY:

AN XY:

34141

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00114

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000187

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.000356

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Oct 03, 2014

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. -

PCDH19-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 22, 2021

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Developmental and epileptic encephalopathy, 9

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 14, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.092

BayesDel_addAF

Benign

-0.64

BayesDel_noAF

Benign

-0.70

Cadd

Benign

Dann

Benign

0.94

FATHMM_MKL

Benign

0.66

LIST_S2

Benign

0.84

T;T;T

M_CAP

Uncertain

0.26

MetaRNN

Benign

0.0063

T;T;T

MetaSVM

Benign

-1.0

MutationTaster

Benign

0.65

D;D;N

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.65

N;N;N

REVEL

Benign

0.020

Sift

Benign

0.29

T;T;T

Sift4G

Benign

0.38

T;T;T

Polyphen

0.0, 0.035

.;B;B

Vest4

0.14

MutPred

0.16

.;Gain of relative solvent accessibility (P = 0.0082);.;

MVP

0.56

MPC

0.50

ClinPred

0.016

GERP RS

3.7

Varity_R

0.10

gMVP

0.20

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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