rs192122222

Positions:

chrX-100408067-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.531G>A(p.Glu177Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000548 in 1,208,819 control chromosomes in the GnomAD database, including 7 homozygotes. There are 190 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 0.00060 ( 0 hom., 23 hem., cov: 24)

Exomes 𝑓: 0.00054 ( 7 hom. 167 hem. )

Consequence

PCDH19
NM_001184880.2 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.0140

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=-0.74).

BP6

Variant X-100408067-C-T is Benign according to our data. Variant chrX-100408067-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 138596.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-100408067-C-T is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-0.014 with no splicing effect.

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000601 (68/113200) while in subpopulation EAS AF= 0.0157 (56/3559). AF 95% confidence interval is 0.0124. There are 0 homozygotes in gnomad4. There are 23 alleles in male gnomad4 subpopulation. Median coverage is 24. This position pass quality control queck.

BS2

High Hemizygotes in GnomAd4 at 23 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCDH19	NM_001184880.2 link	c.531G>A	p.Glu177Glu	synonymous_variant	1/6	ENST00000373034.8	NP_001171809.1	Q8TAB3-1
PCDH19	NM_001105243.2 link	c.531G>A	p.Glu177Glu	synonymous_variant	1/5		NP_001098713.1	Q8TAB3-2B3KU71
PCDH19	NM_020766.3 link	c.531G>A	p.Glu177Glu	synonymous_variant	1/5		NP_065817.2	Q8TAB3-3B3KU71

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
PCDH19	ENST00000373034.8 link	c.531G>A	p.Glu177Glu	synonymous_variant	1/6	1	NM_001184880.2	ENSP00000362125.4	Q8TAB3-1
PCDH19	ENST00000255531.8 link	c.531G>A	p.Glu177Glu	synonymous_variant	1/5	1		ENSP00000255531.7	Q8TAB3-2
PCDH19	ENST00000420881.6 link	c.531G>A	p.Glu177Glu	synonymous_variant	1/5	1		ENSP00000400327.2	Q8TAB3-3

Frequencies

GnomAD3 genomes

AF:

0.000601

AC:

AN:

113146

Hom.:

Cov.:

AF XY:

0.000652

AC XY:

AN XY:

35284

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000276

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0157

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00196

GnomAD3 exomes

AF:

0.00114

AC:

204

AN:

179088

Hom.:

AF XY:

0.000957

AC XY:

AN XY:

65854

show subpopulations

Gnomad AFR exome

AF:

0.000404

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0142

Gnomad SAS exome

AF:

0.000157

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000902

GnomAD4 exome

AF:

0.000543

AC:

595

AN:

1095619

Hom.:

Cov.:

AF XY:

0.000461

AC XY:

167

AN XY:

362207

show subpopulations

Gnomad4 AFR exome

AF:

0.000227

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0165

Gnomad4 SAS exome

AF:

0.0000923

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000356

Gnomad4 OTH exome

AF:

0.00180

GnomAD4 genome

AF:

0.000601

AC:

AN:

113200

Hom.:

Cov.:

AF XY:

0.000651

AC XY:

AN XY:

35348

show subpopulations

Gnomad4 AFR

AF:

0.000192

Gnomad4 AMR

AF:

0.000276

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.0157

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00193

Alfa

AF:

0.000477

Hom.:

Bravo

AF:

0.000756

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 12, 2016	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 02, 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. -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jan 23, 2014	- -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 04, 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. -

Developmental and epileptic encephalopathy, 9

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 22, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.74

CADD

Benign

6.7

DANN

Benign

0.95

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