X-100296597-T-C

Position:

chrX-100296597-T-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001184880.2(PCDH19):c.3127A>G(p.Ile1043Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000223 in 1,209,621 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 7 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I1043F) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000099 ( 0 hom., 2 hem., cov: 23)

Exomes 𝑓: 0.000015 ( 0 hom. 5 hem. )

Consequence

PCDH19
NM_001184880.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 1.39

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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0555318).

BP6

Variant X-100296597-T-C is Benign according to our data. Variant chrX-100296597-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 449713.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0000987 (11/111502) while in subpopulation AMR AF= 0.00104 (11/10575). AF 95% confidence interval is 0.000583. There are 0 homozygotes in gnomad4. There are 2 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.

BS2

High Hemizygotes in GnomAd4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
PCDH19	NM_001184880.2 linkuse as main transcript	c.3127A>G	p.Ile1043Val	missense_variant	6/6	ENST00000373034.8
PCDH19	NM_001105243.2 linkuse as main transcript	c.2986A>G	p.Ile996Val	missense_variant	5/5
PCDH19	NM_020766.3 linkuse as main transcript	c.2983A>G	p.Ile995Val	missense_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCDH19	ENST00000373034.8 linkuse as main transcript	c.3127A>G	p.Ile1043Val	missense_variant	6/6	1	NM_001184880.2	A1	Q8TAB3-1
PCDH19	ENST00000255531.8 linkuse as main transcript	c.2986A>G	p.Ile996Val	missense_variant	5/5	1		P5	Q8TAB3-2
PCDH19	ENST00000420881.6 linkuse as main transcript	c.2983A>G	p.Ile995Val	missense_variant	5/5	1		A1	Q8TAB3-3

Frequencies

GnomAD3 genomes

AF:

0.0000987

AC:

AN:

111449

Hom.:

Cov.:

AF XY:

0.0000595

AC XY:

AN XY:

33617

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00104

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

GnomAD3 exomes

AF:

0.0000441

AC:

AN:

181355

Hom.:

AF XY:

0.0000594

AC XY:

AN XY:

67325

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000256

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000224

GnomAD4 exome

AF:

0.0000146

AC:

AN:

1098119

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

363475

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000284

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000475

Gnomad4 OTH exome

AF:

0.0000434

GnomAD4 genome

AF:

0.0000987

AC:

AN:

111502

Hom.:

Cov.:

AF XY:

0.0000594

AC XY:

AN XY:

33680

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00104

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.000230

ExAC

AF:

0.0000413

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Developmental and epileptic encephalopathy, 9

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 09, 2024

This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1043 of the PCDH19 protein (p.Ile1043Val). This variant is present in population databases (rs189342249, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with PCDH19-related conditions. ClinVar contains an entry for this variant (Variation ID: 449713). 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) performed at Invitae indicates that this missense variant is not expected to disrupt PCDH19 protein function with a negative predictive value of 95%. 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. -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 28, 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. -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

May 03, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.078

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.89

CADD

Benign

DANN

Benign

0.94

FATHMM_MKL

Benign

0.46

LIST_S2

Benign

0.70

T;T;T

M_CAP

Benign

0.012

MetaRNN

Benign

0.056

T;T;T

MetaSVM

Benign

-1.0

MutationTaster

Benign

0.52

N;N;N

PrimateAI

Benign

0.30

PROVEAN

Benign

-0.040

N;N;N

REVEL

Benign

0.090

Sift

Benign

0.54

T;T;T

Sift4G

Benign

0.79

T;T;T

Polyphen

0.0

.;B;B

Vest4

0.048

MutPred

0.25

.;Loss of sheet (P = 0.0084);.;

MVP

0.22

MPC

0.42

ClinPred

0.033

GERP RS

3.1

Varity_R

0.063

gMVP

0.15

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