X-100296324-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001184880.2(PCDH19):c.3400A>C(p.Asn1134His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00069 in 1,210,055 control chromosomes in the GnomAD database, including 6 homozygotes. There are 280 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.00057 ( 0 hom., 18 hem., cov: 23)

Exomes 𝑓: 0.00070 ( 6 hom. 262 hem. )

Consequence

PCDH19
NM_001184880.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 3.01

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0046945214).

BP6

Variant X-100296324-T-G is Benign according to our data. Variant chrX-100296324-T-G is described in ClinVar as [Benign]. Clinvar id is 198129.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-100296324-T-G is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000571 (64/112027) while in subpopulation EAS AF= 0.0173 (61/3530). AF 95% confidence interval is 0.0138. There are 0 homozygotes in gnomad4. There are 18 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.

BS2

High Hemizygotes in GnomAd at 18 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
PCDH19	NM_001184880.2 linkuse as main transcript	c.3400A>C	p.Asn1134His	missense_variant	6/6	ENST00000373034.8
PCDH19	NM_001105243.2 linkuse as main transcript	c.3259A>C	p.Asn1087His	missense_variant	5/5
PCDH19	NM_020766.3 linkuse as main transcript	c.3256A>C	p.Asn1086His	missense_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCDH19	ENST00000373034.8 linkuse as main transcript	c.3400A>C	p.Asn1134His	missense_variant	6/6	1	NM_001184880.2	A1	Q8TAB3-1
PCDH19	ENST00000255531.8 linkuse as main transcript	c.3259A>C	p.Asn1087His	missense_variant	5/5	1		P5	Q8TAB3-2
PCDH19	ENST00000420881.6 linkuse as main transcript	c.3256A>C	p.Asn1086His	missense_variant	5/5	1		A1	Q8TAB3-3
PCDH19	ENST00000464981.1 linkuse as main transcript			upstream_gene_variant		3

Frequencies

GnomAD3 genomes

AF:

0.000572

AC:

AN:

111972

Hom.:

Cov.:

AF XY:

0.000527

AC XY:

AN XY:

34128

show subpopulations

Gnomad AFR

AF:

0.0000325

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000942

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0172

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000662

GnomAD3 exomes

AF:

0.00124

AC:

226

AN:

181623

Hom.:

AF XY:

0.00114

AC XY:

AN XY:

67547

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0162

Gnomad SAS exome

AF:

0.000105

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000246

Gnomad OTH exome

AF:

0.000449

GnomAD4 exome

AF:

0.000702

AC:

771

AN:

1098028

Hom.:

Cov.:

AF XY:

0.000721

AC XY:

262

AN XY:

363388

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0244

Gnomad4 SAS exome

AF:

0.0000923

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000154

Gnomad4 OTH exome

AF:

0.000325

GnomAD4 genome

AF:

0.000571

AC:

AN:

112027

Hom.:

Cov.:

AF XY:

0.000526

AC XY:

AN XY:

34193

show subpopulations

Gnomad4 AFR

AF:

0.0000324

Gnomad4 AMR

AF:

0.0000941

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.0173

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000654

Alfa

AF:

0.000837

Hom.:

Bravo

AF:

0.000450

ExAC

AF:

0.00128

AC:

155

EpiCase

AF:

0.000327

EpiControl

AF:

0.00

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Sep 08, 2014

- -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 02, 2018

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

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

This variant is associated with the following publications: (PMID: 29924869) -

Developmental and epileptic encephalopathy, 9

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 26, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.74

BayesDel_noAF

Benign

-0.82

Cadd

Benign

7.8

Dann

Benign

0.75

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.61

T;T;T

MetaRNN

Benign

0.0047

T;T;T

MetaSVM

Benign

-1.0

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.27

PROVEAN

Benign

-0.61

N;N;N

REVEL

Benign

0.061

Sift

Benign

0.18

T;T;T

Sift4G

Benign

0.16

T;T;T

Polyphen

0.070, 0.12

.;B;B

Vest4

0.15

MVP

0.47

MPC

0.52

ClinPred

0.013

GERP RS

2.8

Varity_R

0.065

gMVP

0.060

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