NM_001184880.2:c.3127A>G

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 1P and 13B. PP2BP4_StrongBP6BS1BS2

The NM_001184880.2(PCDH19):c.3127A>G(p.Ile1043Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000223 in 1,209,621 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 7 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I1043F) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000099 ( 0 hom., 2 hem., cov: 23)

Exomes 𝑓: 0.000015 ( 0 hom. 5 hem. )

Consequence

PCDH19
NM_001184880.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 1.39

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: Benign. The variant received -12 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=0.0555318).

BP6

Variant X-100296597-T-C is Benign according to our data. Variant chrX-100296597-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 449713.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0000987 (11/111502) while in subpopulation AMR AF = 0.00104 (11/10575). AF 95% confidence interval is 0.000583. There are 0 homozygotes in GnomAd4. There are 2 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.

BS2

High AC in GnomAd4 at 11 AD,XL,Unknown gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
PCDH19	NM_001184880.2 link	c.3127A>G	p.Ile1043Val	missense_variant	Exon 6 of 6	ENST00000373034.8	NP_001171809.1
PCDH19	NM_001105243.2 link	c.2986A>G	p.Ile996Val	missense_variant	Exon 5 of 5		NP_001098713.1
PCDH19	NM_020766.3 link	c.2983A>G	p.Ile995Val	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.3127A>G	p.Ile1043Val	missense_variant	Exon 6 of 6	1	NM_001184880.2	ENSP00000362125.4
PCDH19	ENST00000255531.8 link	c.2986A>G	p.Ile996Val	missense_variant	Exon 5 of 5	1		ENSP00000255531.7
PCDH19	ENST00000420881.6 link	c.2983A>G	p.Ile995Val	missense_variant	Exon 5 of 5	1		ENSP00000400327.2

Frequencies

GnomAD3 genomes

AF:

0.0000987

AC:

AN:

111449

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00104

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000441

AC:

AN:

181355

AF XY:

0.0000594

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000256

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000224

GnomAD4 exome

AF:

0.0000146

AC:

AN:

1098119

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

363475

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26400

American (AMR)

AF:

0.000284

AC:

AN:

35205

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19384

East Asian (EAS)

AF:

0.00

AC:

AN:

30200

South Asian (SAS)

AF:

0.00

AC:

AN:

54134

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40531

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4123

European-Non Finnish (NFE)

AF:

0.00000475

AC:

AN:

842045

Other (OTH)

AF:

0.0000434

AC:

AN:

46097

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome 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

GnomAD4 genome

AF:

0.0000987

AC:

AN:

111502

Hom.:

Cov.:

AF XY:

0.0000594

AC XY:

AN XY:

33680

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30673

American (AMR)

AF:

0.00104

AC:

AN:

10575

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2657

East Asian (EAS)

AF:

0.00

AC:

AN:

3543

South Asian (SAS)

AF:

0.00

AC:

AN:

2566

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6008

Middle Eastern (MID)

AF:

0.00

AC:

AN:

215

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53062

Other (OTH)

AF:

0.00

AC:

AN:

1517

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.000230

ExAC

AF:

0.0000413

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Developmental and epileptic encephalopathy, 9

Uncertain:1

Jan 12, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1043 of the PCDH19 protein (p.Ile1043Val). This variant is present in population databases (rs189342249, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with PCDH19-related conditions. ClinVar contains an entry for this variant (Variation ID: 449713). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt PCDH19 protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Inborn genetic diseases

Benign:1

Feb 28, 2018

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely 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

May 03, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.078

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.89

CADD

Benign

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.0

.;T;.

FATHMM_MKL

Benign

0.46

LIST_S2

Benign

0.70

T;T;T

M_CAP

Benign

0.012

MetaRNN

Benign

0.056

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

.;N;.

PhyloP100

1.4

PrimateAI

Benign

0.30

PROVEAN

Benign

-0.040

N;N;N

REVEL

Benign

0.090

Sift

Benign

0.54

T;T;T

Sift4G

Benign

0.79

T;T;T

Vest4

0.048

ClinPred

0.033

GERP RS

3.1

Varity_R

0.063

gMVP

0.15

Mutation Taster

=100/0

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

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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