NM_001184880.2:c.3400A>C

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2BP4_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. 15/20 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:5

Conservation

PhyloP100: 3.01

Publications

8 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 -19 ACMG points.

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=0.0046945214).

BP6

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

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 the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.

BS2

High AC in GnomAd4 at 64 AD,XL,Unknown gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
PCDH19	NM_001184880.2 link	c.3400A>C	p.Asn1134His	missense_variant	Exon 6 of 6	ENST00000373034.8	NP_001171809.1
PCDH19	NM_001105243.2 link	c.3259A>C	p.Asn1087His	missense_variant	Exon 5 of 5		NP_001098713.1
PCDH19	NM_020766.3 link	c.3256A>C	p.Asn1086His	missense_variant	Exon 5 of 5		NP_065817.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
PCDH19	ENST00000373034.8 link	c.3400A>C	p.Asn1134His	missense_variant	Exon 6 of 6	1	NM_001184880.2	ENSP00000362125.4
PCDH19	ENST00000255531.8 link	c.3259A>C	p.Asn1087His	missense_variant	Exon 5 of 5	1		ENSP00000255531.7
PCDH19	ENST00000420881.6 link	c.3256A>C	p.Asn1086His	missense_variant	Exon 5 of 5	1		ENSP00000400327.2
PCDH19	ENST00000464981.1 link	n.-24A>C		upstream_gene_variant		3		ENSP00000479805.1

Frequencies

GnomAD3 genomes

AF:

0.000572

AC:

AN:

111972

Hom.:

Cov.:

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

GnomAD2 exomes

AF:

0.00124

AC:

226

AN:

181623

AF XY:

0.00114

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 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

African (AFR)

AF:

0.00

AC:

AN:

26399

American (AMR)

AF:

0.00

AC:

AN:

35207

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19383

East Asian (EAS)

AF:

0.0244

AC:

737

AN:

30206

South Asian (SAS)

AF:

0.0000923

AC:

AN:

54144

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40531

Middle Eastern (MID)

AF:

0.000242

AC:

AN:

4136

European-Non Finnish (NFE)

AF:

0.0000154

AC:

AN:

841932

Other (OTH)

AF:

0.000325

AC:

AN:

46090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

124

165

206

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome 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

GnomAD4 genome

AF:

0.000571

AC:

AN:

112027

Hom.:

Cov.:

AF XY:

0.000526

AC XY:

AN XY:

34193

show subpopulations

African (AFR)

AF:

0.0000324

AC:

AN:

30867

American (AMR)

AF:

0.0000941

AC:

AN:

10626

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2644

East Asian (EAS)

AF:

0.0173

AC:

AN:

3530

South Asian (SAS)

AF:

0.00

AC:

AN:

2645

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6119

Middle Eastern (MID)

AF:

0.00

AC:

AN:

217

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53161

Other (OTH)

AF:

0.000654

AC:

AN:

1530

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.528

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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

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:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Sep 08, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

Jan 02, 2018

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. -

PCDH19-related disorder

Benign:1

Jun 21, 2024

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided

Benign:1

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Developmental and epileptic encephalopathy, 9

Benign:1

Feb 02, 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

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.74

BayesDel_noAF

Benign

-0.82

CADD

Benign

7.8

(source)

DANN

Benign

0.75

DEOGEN2

Benign

0.027

.;T;.

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.61

T;T;T

MetaRNN

Benign

0.0047

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

.;N;.

PhyloP100

3.0

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

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