rs1953337

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.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

Publications

7 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=-0.6).

BP6

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

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 rank	MANE	Protein
PCDH19	NM_001184880.2 link	c.1627C>T	p.Leu543Leu	synonymous_variant	Exon 1 of 6	ENST00000373034.8	NP_001171809.1
PCDH19	NM_001105243.2 link	c.1627C>T	p.Leu543Leu	synonymous_variant	Exon 1 of 5		NP_001098713.1
PCDH19	NM_020766.3 link	c.1627C>T	p.Leu543Leu	synonymous_variant	Exon 1 of 5		NP_065817.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
PCDH19	ENST00000373034.8 link	c.1627C>T	p.Leu543Leu	synonymous_variant	Exon 1 of 6	1	NM_001184880.2	ENSP00000362125.4
PCDH19	ENST00000255531.8 link	c.1627C>T	p.Leu543Leu	synonymous_variant	Exon 1 of 5	1		ENSP00000255531.7
PCDH19	ENST00000420881.6 link	c.1627C>T	p.Leu543Leu	synonymous_variant	Exon 1 of 5	1		ENSP00000400327.2

Frequencies

GnomAD3 genomes

AF:

0.188

AC:

20972

AN:

111426

Hom.:

2015

Cov.:

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

GnomAD2 exomes

AF:

0.209

AC:

38052

AN:

181671

AF XY:

0.203

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 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

African (AFR)

AF:

0.0414

AC:

1093

AN:

26402

American (AMR)

AF:

0.219

AC:

7727

AN:

35204

Ashkenazi Jewish (ASJ)

AF:

0.169

AC:

3267

AN:

19386

East Asian (EAS)

AF:

0.000298

AC:

AN:

30206

South Asian (SAS)

AF:

0.0872

AC:

4721

AN:

54146

European-Finnish (FIN)

AF:

0.274

AC:

11096

AN:

40494

Middle Eastern (MID)

AF:

0.105

AC:

435

AN:

4137

European-Non Finnish (NFE)

AF:

0.296

AC:

248897

AN:

842085

Other (OTH)

AF:

0.221

AC:

10183

AN:

46091

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

10268

20536

30805

41073

51341

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

8544

17088

25632

34176

42720

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.188

AC:

20970

AN:

111483

Hom.:

2017

Cov.:

AF XY:

0.174

AC XY:

5870

AN XY:

33679

show subpopulations

African (AFR)

AF:

0.0467

AC:

1441

AN:

30828

American (AMR)

AF:

0.174

AC:

1840

AN:

10593

Ashkenazi Jewish (ASJ)

AF:

0.175

AC:

463

AN:

2641

East Asian (EAS)

AF:

0.00142

AC:

AN:

3524

South Asian (SAS)

AF:

0.0619

AC:

163

AN:

2635

European-Finnish (FIN)

AF:

0.257

AC:

1523

AN:

5925

Middle Eastern (MID)

AF:

0.112

AC:

AN:

215

European-Non Finnish (NFE)

AF:

0.285

AC:

15091

AN:

52932

Other (OTH)

AF:

0.157

AC:

238

AN:

1514

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

589

1178

1768

2357

2946

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

216

432

648

864

1080

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.214

Hom.:

7644

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

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 08, 2014

Eurofins Ntd Llc (ga)

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 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. -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Developmental and epileptic encephalopathy, 9

Benign:4

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 22, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 23, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

Mar 02, 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.60

CADD

Benign

7.8

(source)

DANN

Benign

0.75

PhyloP100

3.0

PromoterAI

-0.017

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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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