rs184883626

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.6G>A(p.Glu2Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00635 in 1,162,569 control chromosomes in the GnomAD database, including 413 homozygotes. There are 2,048 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 0.010 ( 52 hom., 372 hem., cov: 23)

Exomes 𝑓: 0.0059 ( 361 hom. 1676 hem. )

Consequence

PCDH19
NM_001184880.2 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.278

Publications

3 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=-0.48).

BP6

Variant X-100408592-C-T is Benign according to our data. Variant chrX-100408592-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 93679.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.278 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0874 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
PCDH19	NM_001184880.2 link	c.6G>A	p.Glu2Glu	synonymous_variant	Exon 1 of 6	ENST00000373034.8	NP_001171809.1
PCDH19	NM_001105243.2 link	c.6G>A	p.Glu2Glu	synonymous_variant	Exon 1 of 5		NP_001098713.1
PCDH19	NM_020766.3 link	c.6G>A	p.Glu2Glu	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.6G>A	p.Glu2Glu	synonymous_variant	Exon 1 of 6	1	NM_001184880.2	ENSP00000362125.4
PCDH19	ENST00000255531.8 link	c.6G>A	p.Glu2Glu	synonymous_variant	Exon 1 of 5	1		ENSP00000255531.7
PCDH19	ENST00000420881.6 link	c.6G>A	p.Glu2Glu	synonymous_variant	Exon 1 of 5	1		ENSP00000400327.2

Frequencies

GnomAD3 genomes

AF:

0.0104

AC:

1157

AN:

111254

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00198

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0918

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0161

Gnomad SAS

AF:

0.00152

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000323

Gnomad OTH

AF:

0.0268

GnomAD2 exomes

AF:

0.0371

AC:

4037

AN:

108779

AF XY:

0.0264

show subpopulations

Gnomad AFR exome

AF:

0.00150

Gnomad AMR exome

AF:

0.179

Gnomad ASJ exome

AF:

0.000160

Gnomad EAS exome

AF:

0.0171

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000249

Gnomad OTH exome

AF:

0.0285

GnomAD4 exome

AF:

0.00591

AC:

6217

AN:

1051268

Hom.:

361

Cov.:

AF XY:

0.00495

AC XY:

1676

AN XY:

338804

show subpopulations

African (AFR)

AF:

0.00166

AC:

AN:

25336

American (AMR)

AF:

0.166

AC:

4964

AN:

29982

Ashkenazi Jewish (ASJ)

AF:

0.000265

AC:

AN:

18849

East Asian (EAS)

AF:

0.0251

AC:

701

AN:

27918

South Asian (SAS)

AF:

0.00149

AC:

AN:

50279

European-Finnish (FIN)

AF:

0.00

AC:

AN:

27210

Middle Eastern (MID)

AF:

0.000551

AC:

AN:

3628

European-Non Finnish (NFE)

AF:

0.000126

AC:

104

AN:

823358

Other (OTH)

AF:

0.00725

AC:

324

AN:

44708

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

274

548

822

1096

1370

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

156

234

312

390

<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:

0.0104

AC:

1162

AN:

111301

Hom.:

Cov.:

AF XY:

0.0111

AC XY:

372

AN XY:

33607

show subpopulations

African (AFR)

AF:

0.00198

AC:

AN:

30855

American (AMR)

AF:

0.0922

AC:

984

AN:

10677

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2624

East Asian (EAS)

AF:

0.0161

AC:

AN:

3471

South Asian (SAS)

AF:

0.00152

AC:

AN:

2631

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6010

Middle Eastern (MID)

AF:

0.00

AC:

AN:

217

European-Non Finnish (NFE)

AF:

0.000323

AC:

AN:

52620

Other (OTH)

AF:

0.0264

AC:

AN:

1514

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

113

150

188

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00636

Hom.:

Bravo

AF:

0.0217

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Aug 22, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jun 11, 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 17, 2013

Genetic Services Laboratory, University of Chicago

Significance:Likely 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

Inborn genetic diseases

Benign:1

Mar 14, 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:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Developmental and epileptic encephalopathy, 9

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.48

CADD

Benign

(source)

DANN

Benign

0.58

PhyloP100

0.28

PromoterAI

-0.082

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