X-100408196-G-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001184880.2(PCDH19):c.402C>A(p.Ile134Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0794 in 1,210,548 control chromosomes in the GnomAD database, including 4,215 homozygotes. There are 33,894 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.077 ( 388 hom., 2925 hem., cov: 25)

Exomes 𝑓: 0.080 ( 3827 hom. 30969 hem. )

Consequence

PCDH19
NM_001184880.2 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -1.89

Publications

6 publications found

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 Gene-Disease associations (from GenCC):

developmental and epileptic encephalopathy, 9
Inheritance: XL, Unknown Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics
X-linked complex neurodevelopmental disorder
Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
Dravet syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

PCDH19 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.89).

BP6

Variant X-100408196-G-T is Benign according to our data. Variant chrX-100408196-G-T is described in ClinVar as [Benign]. Clinvar id is 93677.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.89 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.269 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCDH19	NM_001184880.2 link	c.402C>A	p.Ile134Ile	synonymous_variant	Exon 1 of 6	ENST00000373034.8	NP_001171809.1	Q8TAB3-1
PCDH19	NM_001105243.2 link	c.402C>A	p.Ile134Ile	synonymous_variant	Exon 1 of 5		NP_001098713.1	Q8TAB3-2B3KU71
PCDH19	NM_020766.3 link	c.402C>A	p.Ile134Ile	synonymous_variant	Exon 1 of 5		NP_065817.2	Q8TAB3-3B3KU71

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PCDH19	ENST00000373034.8 link	c.402C>A	p.Ile134Ile	synonymous_variant	Exon 1 of 6	1	NM_001184880.2	ENSP00000362125.4	Q8TAB3-1
PCDH19	ENST00000255531.8 link	c.402C>A	p.Ile134Ile	synonymous_variant	Exon 1 of 5	1		ENSP00000255531.7	Q8TAB3-2
PCDH19	ENST00000420881.6 link	c.402C>A	p.Ile134Ile	synonymous_variant	Exon 1 of 5	1		ENSP00000400327.2	Q8TAB3-3

Frequencies

GnomAD3 genomes

AF:

0.0772

AC:

8676

AN:

112357

Hom.:

388

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0372

Gnomad AMI

AF:

0.0145

Gnomad AMR

AF:

0.203

Gnomad ASJ

AF:

0.0754

Gnomad EAS

AF:

0.284

Gnomad SAS

AF:

0.253

Gnomad FIN

AF:

0.0377

Gnomad MID

AF:

0.0840

Gnomad NFE

AF:

0.0578

Gnomad OTH

AF:

0.0968

GnomAD2 exomes

AF:

0.131

AC:

23719

AN:

181650

AF XY:

0.128

show subpopulations

Gnomad AFR exome

AF:

0.0368

Gnomad AMR exome

AF:

0.291

Gnomad ASJ exome

AF:

0.0730

Gnomad EAS exome

AF:

0.294

Gnomad FIN exome

AF:

0.0440

Gnomad NFE exome

AF:

0.0576

Gnomad OTH exome

AF:

0.112

GnomAD4 exome

AF:

0.0796

AC:

87447

AN:

1098136

Hom.:

3827

Cov.:

AF XY:

0.0852

AC XY:

30969

AN XY:

363502

show subpopulations

African (AFR)

AF:

0.0362

AC:

955

AN:

26403

American (AMR)

AF:

0.280

AC:

9852

AN:

35206

Ashkenazi Jewish (ASJ)

AF:

0.0750

AC:

1454

AN:

19385

East Asian (EAS)

AF:

0.266

AC:

8020

AN:

30203

South Asian (SAS)

AF:

0.244

AC:

13233

AN:

54149

European-Finnish (FIN)

AF:

0.0474

AC:

1919

AN:

40470

Middle Eastern (MID)

AF:

0.0870

AC:

360

AN:

4137

European-Non Finnish (NFE)

AF:

0.0561

AC:

47256

AN:

842088

Other (OTH)

AF:

0.0954

AC:

4398

AN:

46095

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

3894

7787

11681

15574

19468

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0772

AC:

8679

AN:

112412

Hom.:

388

Cov.:

AF XY:

0.0845

AC XY:

2925

AN XY:

34604

show subpopulations

African (AFR)

AF:

0.0372

AC:

1155

AN:

31072

American (AMR)

AF:

0.203

AC:

2179

AN:

10753

Ashkenazi Jewish (ASJ)

AF:

0.0754

AC:

200

AN:

2652

East Asian (EAS)

AF:

0.284

AC:

990

AN:

3485

South Asian (SAS)

AF:

0.252

AC:

668

AN:

2648

European-Finnish (FIN)

AF:

0.0377

AC:

233

AN:

6187

Middle Eastern (MID)

AF:

0.0876

AC:

AN:

217

European-Non Finnish (NFE)

AF:

0.0578

AC:

3075

AN:

53170

Other (OTH)

AF:

0.0975

AC:

150

AN:

1539

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

270

539

809

1078

1348

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0475

Hom.:

466

Bravo

AF:

0.0912

EpiCase

AF:

0.0607

EpiControl

AF:

0.0578

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Mar 09, 2012

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Jan 10, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 15, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 34% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 32. Only high quality variants are reported. -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Developmental and epileptic encephalopathy, 9

Benign:3

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 05, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

Jan 08, 2016

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.89

CADD

Benign

0.63

(source)

DANN

Benign

0.88

PhyloP100

-1.9

PromoterAI

-0.020

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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X-100408196-G-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over