chrX-100406971-G-A

Position:

chrX-100406971-G-A

Variant summary

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

The NM_001184880.2(PCDH19):c.1627C>T(p.Leu543Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.255 in 1,209,634 control chromosomes in the GnomAD database, including 30,302 homozygotes. There are 98,094 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.19 ( 2017 hom., 5870 hem., cov: 23)

Exomes 𝑓: 0.26 ( 28285 hom. 92224 hem. )

Consequence

PCDH19
NM_001184880.2 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: 2.97

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=-0.6).

BP6

Variant X-100406971-G-A is Benign according to our data. Variant chrX-100406971-G-A is described in ClinVar as [Benign]. Clinvar id is 93671.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-100406971-G-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=2.97 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.281 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.1627C>T	p.Leu543Leu	synonymous_variant	1/6	ENST00000373034.8	NP_001171809.1	Q8TAB3-1
PCDH19	NM_001105243.2 linkuse as main transcript	c.1627C>T	p.Leu543Leu	synonymous_variant	1/5		NP_001098713.1	Q8TAB3-2B3KU71
PCDH19	NM_020766.3 linkuse as main transcript	c.1627C>T	p.Leu543Leu	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.1627C>T	p.Leu543Leu	synonymous_variant	1/6	1	NM_001184880.2	ENSP00000362125.4	Q8TAB3-1
PCDH19	ENST00000255531.8 linkuse as main transcript	c.1627C>T	p.Leu543Leu	synonymous_variant	1/5	1		ENSP00000255531.7	Q8TAB3-2
PCDH19	ENST00000420881.6 linkuse as main transcript	c.1627C>T	p.Leu543Leu	synonymous_variant	1/5	1		ENSP00000400327.2	Q8TAB3-3

Frequencies

GnomAD3 genomes

AF:

0.188

AC:

20972

AN:

111426

Hom.:

2015

Cov.:

AF XY:

0.174

AC XY:

5865

AN XY:

33612

show subpopulations

Gnomad AFR

AF:

0.0468

Gnomad AMI

AF:

0.269

Gnomad AMR

AF:

0.174

Gnomad ASJ

AF:

0.175

Gnomad EAS

AF:

0.00141

Gnomad SAS

AF:

0.0602

Gnomad FIN

AF:

0.257

Gnomad MID

AF:

0.114

Gnomad NFE

AF:

0.285

Gnomad OTH

AF:

0.159

GnomAD3 exomes

AF:

0.209

AC:

38052

AN:

181671

Hom.:

3225

AF XY:

0.203

AC XY:

13692

AN XY:

67489

show subpopulations

Gnomad AFR exome

AF:

0.0453

Gnomad AMR exome

AF:

0.225

Gnomad ASJ exome

AF:

0.169

Gnomad EAS exome

AF:

0.0000738

Gnomad SAS exome

AF:

0.0821

Gnomad FIN exome

AF:

0.275

Gnomad NFE exome

AF:

0.284

Gnomad OTH exome

AF:

0.225

GnomAD4 exome

AF:

0.262

AC:

287428

AN:

1098151

Hom.:

28285

Cov.:

AF XY:

0.254

AC XY:

92224

AN XY:

363521

show subpopulations

Gnomad4 AFR exome

AF:

0.0414

Gnomad4 AMR exome

AF:

0.219

Gnomad4 ASJ exome

AF:

0.169

Gnomad4 EAS exome

AF:

0.000298

Gnomad4 SAS exome

AF:

0.0872

Gnomad4 FIN exome

AF:

0.274

Gnomad4 NFE exome

AF:

0.296

Gnomad4 OTH exome

AF:

0.221

GnomAD4 genome

AF:

0.188

AC:

20970

AN:

111483

Hom.:

2017

Cov.:

AF XY:

0.174

AC XY:

5870

AN XY:

33679

show subpopulations

Gnomad4 AFR

AF:

0.0467

Gnomad4 AMR

AF:

0.174

Gnomad4 ASJ

AF:

0.175

Gnomad4 EAS

AF:

0.00142

Gnomad4 SAS

AF:

0.0619

Gnomad4 FIN

AF:

0.257

Gnomad4 NFE

AF:

0.285

Gnomad4 OTH

AF:

0.157

Alfa

AF:

0.253

Hom.:

5451

Bravo

AF:

0.179

EpiCase

AF:

0.258

EpiControl

AF:

0.253

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
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 30% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 28. Only high quality variants are reported. -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 08, 2014	- -

Developmental and epileptic encephalopathy, 9

Benign:4

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Dec 23, 2021	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 02, 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.60

CADD

Benign

7.8

DANN

Benign

0.75

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