X-100407245-C-T

Position:

chrX-100407245-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.1353G>A(p.Pro451=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000496 in 1,210,131 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 21 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 0.00029 ( 0 hom., 11 hem., cov: 24)

Exomes 𝑓: 0.000025 ( 0 hom. 10 hem. )

Consequence

PCDH19
NM_001184880.2 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -6.46

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=-0.75).

BP6

Variant X-100407245-C-T is Benign according to our data. Variant chrX-100407245-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 379558.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-100407245-C-T is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=-6.46 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000286 (32/111910) while in subpopulation AFR AF= 0.00078 (24/30770). AF 95% confidence interval is 0.000538. There are 0 homozygotes in gnomad4. There are 11 alleles in male gnomad4 subpopulation. Median coverage is 24. This position pass quality control queck.

BS2

High Hemizygotes in GnomAd4 at 11 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
PCDH19	NM_001184880.2 linkuse as main transcript	c.1353G>A	p.Pro451=	synonymous_variant	1/6	ENST00000373034.8	NP_001171809.1
PCDH19	NM_001105243.2 linkuse as main transcript	c.1353G>A	p.Pro451=	synonymous_variant	1/5		NP_001098713.1
PCDH19	NM_020766.3 linkuse as main transcript	c.1353G>A	p.Pro451=	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.1353G>A	p.Pro451=	synonymous_variant	1/6	1	NM_001184880.2	ENSP00000362125	A1	Q8TAB3-1
PCDH19	ENST00000255531.8 linkuse as main transcript	c.1353G>A	p.Pro451=	synonymous_variant	1/5	1		ENSP00000255531	P5	Q8TAB3-2
PCDH19	ENST00000420881.6 linkuse as main transcript	c.1353G>A	p.Pro451=	synonymous_variant	1/5	1		ENSP00000400327	A1	Q8TAB3-3

Frequencies

GnomAD3 genomes

AF:

0.000286

AC:

AN:

111910

Hom.:

Cov.:

AF XY:

0.000323

AC XY:

AN XY:

34076

show subpopulations

Gnomad AFR

AF:

0.000780

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000658

GnomAD3 exomes

AF:

0.0000715

AC:

AN:

181839

Hom.:

AF XY:

0.0000591

AC XY:

AN XY:

67677

show subpopulations

Gnomad AFR exome

AF:

0.000726

Gnomad AMR exome

AF:

0.000110

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000224

GnomAD4 exome

AF:

0.0000255

AC:

AN:

1098221

Hom.:

Cov.:

AF XY:

0.0000275

AC XY:

AN XY:

363575

show subpopulations

Gnomad4 AFR exome

AF:

0.000492

Gnomad4 AMR exome

AF:

0.000142

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000185

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.000195

GnomAD4 genome

AF:

0.000286

AC:

AN:

111910

Hom.:

Cov.:

AF XY:

0.000323

AC XY:

AN XY:

34076

show subpopulations

Gnomad4 AFR

AF:

0.000780

Gnomad4 AMR

AF:

0.000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000658

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.000480

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 10, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 14, 2018	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 17, 2017

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. -

PCDH19-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 18, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Developmental and epileptic encephalopathy, 9

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 03, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.75

CADD

Benign

0.15

DANN

Benign

0.78

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