rs1304917337

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2PP2BP4

The NM_001184880.2(PCDH19):c.2391C>G(p.Asp797Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,208,242 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.0000089 ( 0 hom., 0 hem., cov: 23)

Exomes 𝑓: 0.0000018 ( 0 hom. 1 hem. )

Consequence

PCDH19
NM_001184880.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 2.42

Publications

0 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: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 107 curated pathogenic missense variants (we use a threshold of 10). The gene has 20 curated benign missense variants. Gene score misZ: 2.5929 (below the threshold of 3.09). Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to Dravet syndrome, developmental and epileptic encephalopathy, 9, X-linked complex neurodevelopmental disorder.

BP4

Computational evidence support a benign effect (MetaRNN=0.3033027).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001184880.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PCDH19	NM_001184880.2	MANE Select	c.2391C>G	p.Asp797Glu	missense	Exon 3 of 6	NP_001171809.1
PCDH19	NM_001105243.2		c.2250C>G	p.Asp750Glu	missense	Exon 2 of 5	NP_001098713.1
PCDH19	NM_020766.3		c.2250C>G	p.Asp750Glu	missense	Exon 2 of 5	NP_065817.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PCDH19	ENST00000373034.8	TSL:1 MANE Select	c.2391C>G	p.Asp797Glu	missense	Exon 3 of 6	ENSP00000362125.4
PCDH19	ENST00000255531.8	TSL:1	c.2250C>G	p.Asp750Glu	missense	Exon 2 of 5	ENSP00000255531.7
PCDH19	ENST00000420881.6	TSL:1	c.2250C>G	p.Asp750Glu	missense	Exon 2 of 5	ENSP00000400327.2

Frequencies

GnomAD3 genomes

AF:

0.00000892

AC:

AN:

112066

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000188

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000550

AC:

AN:

181658

AF XY:

0.0000148

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000123

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000182

AC:

AN:

1096176

Hom.:

Cov.:

AF XY:

0.00000277

AC XY:

AN XY:

361568

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26370

American (AMR)

AF:

0.00

AC:

AN:

35207

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19376

East Asian (EAS)

AF:

0.00

AC:

AN:

30200

South Asian (SAS)

AF:

0.00

AC:

AN:

54099

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40530

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4128

European-Non Finnish (NFE)

AF:

0.00000238

AC:

AN:

840249

Other (OTH)

AF:

0.00

AC:

AN:

46017

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.00000892

AC:

AN:

112066

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34218

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30796

American (AMR)

AF:

0.00

AC:

AN:

10626

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2645

East Asian (EAS)

AF:

0.00

AC:

AN:

3543

South Asian (SAS)

AF:

0.00

AC:

AN:

2669

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6134

Middle Eastern (MID)

AF:

0.00

AC:

AN:

239

European-Non Finnish (NFE)

AF:

0.0000188

AC:

AN:

53204

Other (OTH)

AF:

0.00

AC:

AN:

1522

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000189

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Developmental and epileptic encephalopathy, 9 (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.49

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Uncertain

0.060

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.024

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.94

M_CAP

Benign

0.034

MetaRNN

Benign

0.30

MetaSVM

Benign

-0.89

MutationAssessor

Benign

0.69

PhyloP100

2.4

PrimateAI

Pathogenic

0.82

PROVEAN

Benign

-0.73

REVEL

Benign

0.22

Sift

Benign

0.27

Sift4G

Benign

0.44

Polyphen

0.99

Vest4

0.50

MutPred

0.27

Loss of sheet (P = 0.0228)

MVP

0.94

MPC

1.2

ClinPred

0.57

GERP RS

4.9

Varity_R

0.23

gMVP

0.31

Mutation Taster

=91/9

polymorphism

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over