X-100406915-C-T

Position:

chrX-100406915-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_001184880.2(PCDH19):c.1683G>A(p.Pro561=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00327 in 1,210,006 control chromosomes in the GnomAD database, including 8 homozygotes. There are 1,265 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0027 ( 0 hom., 68 hem., cov: 23)

Exomes 𝑓: 0.0033 ( 8 hom. 1197 hem. )

Consequence

PCDH19
NM_001184880.2 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -2.47

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.55).

BP6

Variant X-100406915-C-T is Benign according to our data. Variant chrX-100406915-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 93672.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-100406915-C-T is described in Lovd as [Likely_benign]. Variant chrX-100406915-C-T is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-2.47 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00273 (305/111879) while in subpopulation NFE AF= 0.00431 (229/53104). AF 95% confidence interval is 0.00385. There are 0 homozygotes in gnomad4. There are 68 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.

BS2

High Hemizygotes in GnomAd4 at 68 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
PCDH19	NM_001184880.2 linkuse as main transcript	c.1683G>A	p.Pro561=	synonymous_variant	1/6	ENST00000373034.8	NP_001171809.1
PCDH19	NM_001105243.2 linkuse as main transcript	c.1683G>A	p.Pro561=	synonymous_variant	1/5		NP_001098713.1
PCDH19	NM_020766.3 linkuse as main transcript	c.1683G>A	p.Pro561=	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.1683G>A	p.Pro561=	synonymous_variant	1/6	1	NM_001184880.2	ENSP00000362125	A1	Q8TAB3-1
PCDH19	ENST00000255531.8 linkuse as main transcript	c.1683G>A	p.Pro561=	synonymous_variant	1/5	1		ENSP00000255531	P5	Q8TAB3-2
PCDH19	ENST00000420881.6 linkuse as main transcript	c.1683G>A	p.Pro561=	synonymous_variant	1/5	1		ENSP00000400327	A1	Q8TAB3-3

Frequencies

GnomAD3 genomes

AF:

0.00273

AC:

305

AN:

111825

Hom.:

Cov.:

AF XY:

0.00200

AC XY:

AN XY:

33995

show subpopulations

Gnomad AFR

AF:

0.000228

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00358

Gnomad ASJ

AF:

0.00716

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000377

Gnomad FIN

AF:

0.000822

Gnomad MID

AF:

0.00424

Gnomad NFE

AF:

0.00431

Gnomad OTH

AF:

0.00335

GnomAD3 exomes

AF:

0.00285

AC:

517

AN:

181625

Hom.:

AF XY:

0.00258

AC XY:

174

AN XY:

67473

show subpopulations

Gnomad AFR exome

AF:

0.000161

Gnomad AMR exome

AF:

0.00197

Gnomad ASJ exome

AF:

0.00628

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000315

Gnomad FIN exome

AF:

0.00138

Gnomad NFE exome

AF:

0.00446

Gnomad OTH exome

AF:

0.00515

GnomAD4 exome

AF:

0.00333

AC:

3657

AN:

1098127

Hom.:

Cov.:

AF XY:

0.00329

AC XY:

1197

AN XY:

363487

show subpopulations

Gnomad4 AFR exome

AF:

0.0000758

Gnomad4 AMR exome

AF:

0.00227

Gnomad4 ASJ exome

AF:

0.00712

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000425

Gnomad4 FIN exome

AF:

0.00202

Gnomad4 NFE exome

AF:

0.00372

Gnomad4 OTH exome

AF:

0.00399

GnomAD4 genome

AF:

0.00273

AC:

305

AN:

111879

Hom.:

Cov.:

AF XY:

0.00200

AC XY:

AN XY:

34059

show subpopulations

Gnomad4 AFR

AF:

0.000227

Gnomad4 AMR

AF:

0.00358

Gnomad4 ASJ

AF:

0.00716

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000378

Gnomad4 FIN

AF:

0.000822

Gnomad4 NFE

AF:

0.00431

Gnomad4 OTH

AF:

0.00330

Alfa

AF:

0.00393

Hom.:

Bravo

AF:

0.00352

EpiCase

AF:

0.00447

EpiControl

AF:

0.00551

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2021	- -

Developmental and epileptic encephalopathy, 9

Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 13, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 28, 2024	- -
Benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	May 05, 2016	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 16, 2013	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 01, 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. -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 27, 2016

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.55

CADD

Benign

4.4

DANN

Benign

0.86

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