NM_001184880.2:c.545G>C

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 3P and 6B. PM1PP2BP4BP6BS2

The NM_001184880.2(PCDH19):c.545G>C(p.Gly182Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0000796 in 113,113 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 hemizygotes in GnomAD. In-silico tool predicts 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. G182R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000080 ( 0 hom., 4 hem., cov: 24)

Exomes 𝑓: 0.0000055 ( 0 hom. 4 hem. )

Failed GnomAD Quality Control

Consequence

PCDH19
NM_001184880.2 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 4.96

Publications

1 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: Likely_benign. The variant received -3 ACMG points.

PM1

In a domain Cadherin 2 (size 108) in uniprot entity PCD19_HUMAN there are 34 pathogenic changes around while only 2 benign (94%) in NM_001184880.2

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=0.30897903).

BP6

Variant X-100408053-C-G is Benign according to our data. Variant chrX-100408053-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 167421.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

BS2

High AC in GnomAd4 at 9 AD,XL,Unknown gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCDH19	NM_001184880.2 link	c.545G>C	p.Gly182Ala	missense_variant	Exon 1 of 6	ENST00000373034.8	NP_001171809.1	Q8TAB3-1
PCDH19	NM_001105243.2 link	c.545G>C	p.Gly182Ala	missense_variant	Exon 1 of 5		NP_001098713.1	Q8TAB3-2B3KU71
PCDH19	NM_020766.3 link	c.545G>C	p.Gly182Ala	missense_variant	Exon 1 of 5		NP_065817.2	Q8TAB3-3B3KU71

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PCDH19	ENST00000373034.8 link	c.545G>C	p.Gly182Ala	missense_variant	Exon 1 of 6	1	NM_001184880.2	ENSP00000362125.4	Q8TAB3-1
PCDH19	ENST00000255531.8 link	c.545G>C	p.Gly182Ala	missense_variant	Exon 1 of 5	1		ENSP00000255531.7	Q8TAB3-2
PCDH19	ENST00000420881.6 link	c.545G>C	p.Gly182Ala	missense_variant	Exon 1 of 5	1		ENSP00000400327.2	Q8TAB3-3

Frequencies

GnomAD3 genomes

AF:

0.0000796

AC:

AN:

113113

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000257

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:

0.0000187

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000112

AC:

AN:

178452

AF XY:

0.0000305

show subpopulations

Gnomad AFR exome

AF:

0.000162

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000548

AC:

AN:

1094944

Hom.:

Cov.:

AF XY:

0.0000111

AC XY:

AN XY:

361904

show subpopulations

African (AFR)

AF:

0.000114

AC:

AN:

26402

American (AMR)

AF:

0.00

AC:

AN:

35201

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19384

East Asian (EAS)

AF:

0.00

AC:

AN:

30205

South Asian (SAS)

AF:

0.00

AC:

AN:

54149

European-Finnish (FIN)

AF:

0.00

AC:

AN:

37277

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4137

European-Non Finnish (NFE)

AF:

0.00000356

AC:

AN:

842116

Other (OTH)

AF:

0.00

AC:

AN:

46073

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

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:

0.0000796

AC:

AN:

113113

Hom.:

Cov.:

AF XY:

0.000113

AC XY:

AN XY:

35269

show subpopulations

African (AFR)

AF:

0.000257

AC:

AN:

31159

American (AMR)

AF:

0.00

AC:

AN:

10852

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2660

East Asian (EAS)

AF:

0.00

AC:

AN:

3559

South Asian (SAS)

AF:

0.00

AC:

AN:

2783

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6265

Middle Eastern (MID)

AF:

0.00

AC:

AN:

240

European-Non Finnish (NFE)

AF:

0.0000187

AC:

AN:

53381

Other (OTH)

AF:

0.00

AC:

AN:

1529

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.515

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:

0.0000712

Hom.:

Bravo

AF:

0.0000453

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

May 01, 2019

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 04, 2014

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Developmental and epileptic encephalopathy, 9

Uncertain:1

Nov 19, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 182 of the PCDH19 protein (p.Gly182Ala). This variant is present in population databases (rs727504067, gnomAD 0.02%). 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: 167421). 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) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PCDH19 protein function. 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.42

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.36

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.060

.;T;.

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.93

D;D;D

M_CAP

Uncertain

0.13

MetaRNN

Benign

0.31

T;T;T

MetaSVM

Benign

-0.83

MutationAssessor

Benign

-0.85

N;N;N

PhyloP100

5.0

PrimateAI

Uncertain

0.78

PROVEAN

Benign

-1.8

N;N;N

REVEL

Benign

0.22

Sift

Benign

0.041

D;D;D

Sift4G

Uncertain

0.027

D;D;D

Polyphen

1.0

.;D;D

Vest4

0.59

MutPred

0.26

Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);

MVP

0.79

MPC

2.5

ClinPred

0.38

GERP RS

5.7

Varity_R

0.68

gMVP

0.73

Mutation Taster

=71/29

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