rs184883626

Positions:

chrX-100408592-C-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.6G>A(p.Glu2Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00635 in 1,162,569 control chromosomes in the GnomAD database, including 413 homozygotes. There are 2,048 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 0.010 ( 52 hom., 372 hem., cov: 23)

Exomes 𝑓: 0.0059 ( 361 hom. 1676 hem. )

Consequence

PCDH19
NM_001184880.2 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.278

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=-0.48).

BP6

Variant X-100408592-C-T is Benign according to our data. Variant chrX-100408592-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 93679.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-100408592-C-T is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=0.278 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0874 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCDH19	NM_001184880.2 linkuse as main transcript	c.6G>A	p.Glu2Glu	synonymous_variant	1/6	ENST00000373034.8	NP_001171809.1	Q8TAB3-1
PCDH19	NM_001105243.2 linkuse as main transcript	c.6G>A	p.Glu2Glu	synonymous_variant	1/5		NP_001098713.1	Q8TAB3-2B3KU71
PCDH19	NM_020766.3 linkuse as main transcript	c.6G>A	p.Glu2Glu	synonymous_variant	1/5		NP_065817.2	Q8TAB3-3B3KU71

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
PCDH19	ENST00000373034.8 linkuse as main transcript	c.6G>A	p.Glu2Glu	synonymous_variant	1/6	1	NM_001184880.2	ENSP00000362125.4	Q8TAB3-1
PCDH19	ENST00000255531.8 linkuse as main transcript	c.6G>A	p.Glu2Glu	synonymous_variant	1/5	1		ENSP00000255531.7	Q8TAB3-2
PCDH19	ENST00000420881.6 linkuse as main transcript	c.6G>A	p.Glu2Glu	synonymous_variant	1/5	1		ENSP00000400327.2	Q8TAB3-3

Frequencies

GnomAD3 genomes

AF:

0.0104

AC:

1157

AN:

111254

Hom.:

Cov.:

AF XY:

0.0110

AC XY:

370

AN XY:

33550

show subpopulations

Gnomad AFR

AF:

0.00198

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0918

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0161

Gnomad SAS

AF:

0.00152

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000323

Gnomad OTH

AF:

0.0268

GnomAD3 exomes

AF:

0.0371

AC:

4037

AN:

108779

Hom.:

299

AF XY:

0.0264

AC XY:

960

AN XY:

36299

show subpopulations

Gnomad AFR exome

AF:

0.00150

Gnomad AMR exome

AF:

0.179

Gnomad ASJ exome

AF:

0.000160

Gnomad EAS exome

AF:

0.0171

Gnomad SAS exome

AF:

0.00153

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000249

Gnomad OTH exome

AF:

0.0285

GnomAD4 exome

AF:

0.00591

AC:

6217

AN:

1051268

Hom.:

361

Cov.:

AF XY:

0.00495

AC XY:

1676

AN XY:

338804

show subpopulations

Gnomad4 AFR exome

AF:

0.00166

Gnomad4 AMR exome

AF:

0.166

Gnomad4 ASJ exome

AF:

0.000265

Gnomad4 EAS exome

AF:

0.0251

Gnomad4 SAS exome

AF:

0.00149

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000126

Gnomad4 OTH exome

AF:

0.00725

GnomAD4 genome

AF:

0.0104

AC:

1162

AN:

111301

Hom.:

Cov.:

AF XY:

0.0111

AC XY:

372

AN XY:

33607

show subpopulations

Gnomad4 AFR

AF:

0.00198

Gnomad4 AMR

AF:

0.0922

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.0161

Gnomad4 SAS

AF:

0.00152

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000323

Gnomad4 OTH

AF:

0.0264

Alfa

AF:

0.00636

Hom.:

Bravo

AF:

0.0217

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 11, 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. -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jan 17, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 22, 2014	- -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 14, 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

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Developmental and epileptic encephalopathy, 9

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.48

CADD

Benign

DANN

Benign

0.58

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