X-100408196-G-T

Position:

chrX-100408196-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001184880.2(PCDH19):c.402C>A(p.Ile134=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0794 in 1,210,548 control chromosomes in the GnomAD database, including 4,215 homozygotes. There are 33,894 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.077 ( 388 hom., 2925 hem., cov: 25)

Exomes 𝑓: 0.080 ( 3827 hom. 30969 hem. )

Consequence

PCDH19
NM_001184880.2 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -1.89

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.89).

BP6

Variant X-100408196-G-T is Benign according to our data. Variant chrX-100408196-G-T is described in ClinVar as [Benign]. Clinvar id is 93677.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-100408196-G-T is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-1.89 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.269 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.402C>A	p.Ile134=	synonymous_variant	1/6	ENST00000373034.8	NP_001171809.1
PCDH19	NM_001105243.2 linkuse as main transcript	c.402C>A	p.Ile134=	synonymous_variant	1/5		NP_001098713.1
PCDH19	NM_020766.3 linkuse as main transcript	c.402C>A	p.Ile134=	synonymous_variant	1/5		NP_065817.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCDH19	ENST00000373034.8 linkuse as main transcript	c.402C>A	p.Ile134=	synonymous_variant	1/6	1	NM_001184880.2	ENSP00000362125	A1	Q8TAB3-1
PCDH19	ENST00000255531.8 linkuse as main transcript	c.402C>A	p.Ile134=	synonymous_variant	1/5	1		ENSP00000255531	P5	Q8TAB3-2
PCDH19	ENST00000420881.6 linkuse as main transcript	c.402C>A	p.Ile134=	synonymous_variant	1/5	1		ENSP00000400327	A1	Q8TAB3-3

Frequencies

GnomAD3 genomes

AF:

0.0772

AC:

8676

AN:

112357

Hom.:

388

Cov.:

AF XY:

0.0845

AC XY:

2920

AN XY:

34539

show subpopulations

Gnomad AFR

AF:

0.0372

Gnomad AMI

AF:

0.0145

Gnomad AMR

AF:

0.203

Gnomad ASJ

AF:

0.0754

Gnomad EAS

AF:

0.284

Gnomad SAS

AF:

0.253

Gnomad FIN

AF:

0.0377

Gnomad MID

AF:

0.0840

Gnomad NFE

AF:

0.0578

Gnomad OTH

AF:

0.0968

GnomAD3 exomes

AF:

0.131

AC:

23719

AN:

181650

Hom.:

1781

AF XY:

0.128

AC XY:

8666

AN XY:

67492

show subpopulations

Gnomad AFR exome

AF:

0.0368

Gnomad AMR exome

AF:

0.291

Gnomad ASJ exome

AF:

0.0730

Gnomad EAS exome

AF:

0.294

Gnomad SAS exome

AF:

0.257

Gnomad FIN exome

AF:

0.0440

Gnomad NFE exome

AF:

0.0576

Gnomad OTH exome

AF:

0.112

GnomAD4 exome

AF:

0.0796

AC:

87447

AN:

1098136

Hom.:

3827

Cov.:

AF XY:

0.0852

AC XY:

30969

AN XY:

363502

show subpopulations

Gnomad4 AFR exome

AF:

0.0362

Gnomad4 AMR exome

AF:

0.280

Gnomad4 ASJ exome

AF:

0.0750

Gnomad4 EAS exome

AF:

0.266

Gnomad4 SAS exome

AF:

0.244

Gnomad4 FIN exome

AF:

0.0474

Gnomad4 NFE exome

AF:

0.0561

Gnomad4 OTH exome

AF:

0.0954

GnomAD4 genome

AF:

0.0772

AC:

8679

AN:

112412

Hom.:

388

Cov.:

AF XY:

0.0845

AC XY:

2925

AN XY:

34604

show subpopulations

Gnomad4 AFR

AF:

0.0372

Gnomad4 AMR

AF:

0.203

Gnomad4 ASJ

AF:

0.0754

Gnomad4 EAS

AF:

0.284

Gnomad4 SAS

AF:

0.252

Gnomad4 FIN

AF:

0.0377

Gnomad4 NFE

AF:

0.0578

Gnomad4 OTH

AF:

0.0975

Alfa

AF:

0.0475

Hom.:

466

Bravo

AF:

0.0912

EpiCase

AF:

0.0607

EpiControl

AF:

0.0578

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jul 15, 2024	This variant is classified as Benign based on local population frequency. This variant was detected in 34% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 32. Only high quality variants are reported. -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 10, 2014	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 09, 2012	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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Developmental and epileptic encephalopathy, 9

Benign:3

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 05, 2021	- -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 08, 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. -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.89

CADD

Benign

0.63

DANN

Benign

0.88

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