rs371109150

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001184880.2(PCDH19):c.2975C>T(p.Ala992Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000091 in 1,209,235 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A992E) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000036 ( 0 hom., 1 hem., cov: 22)

Exomes 𝑓: 0.0000064 ( 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: 6.52

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.14945772).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
PCDH19	NM_001184880.2 linkuse as main transcript	c.2975C>T	p.Ala992Val	missense_variant	6/6	ENST00000373034.8
PCDH19	NM_001105243.2 linkuse as main transcript	c.2834C>T	p.Ala945Val	missense_variant	5/5
PCDH19	NM_020766.3 linkuse as main transcript	c.2831C>T	p.Ala944Val	missense_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCDH19	ENST00000373034.8 linkuse as main transcript	c.2975C>T	p.Ala992Val	missense_variant	6/6	1	NM_001184880.2	A1	Q8TAB3-1
PCDH19	ENST00000255531.8 linkuse as main transcript	c.2834C>T	p.Ala945Val	missense_variant	5/5	1		P5	Q8TAB3-2
PCDH19	ENST00000420881.6 linkuse as main transcript	c.2831C>T	p.Ala944Val	missense_variant	5/5	1		A1	Q8TAB3-3

Frequencies

GnomAD3 genomes

AF:

0.0000359

AC:

AN:

111514

Hom.:

Cov.:

AF XY:

0.0000297

AC XY:

AN XY:

33670

show subpopulations

Gnomad AFR

AF:

0.0000979

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

GnomAD3 exomes

AF:

0.0000330

AC:

AN:

181576

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

67528

show subpopulations

Gnomad AFR exome

AF:

0.000323

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000738

Gnomad SAS 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:

0.00000638

AC:

AN:

1097721

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

363091

show subpopulations

Gnomad4 AFR exome

AF:

0.0000758

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000331

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000356

Gnomad4 OTH exome

AF:

0.0000217

GnomAD4 genome

AF:

0.0000359

AC:

AN:

111514

Hom.:

Cov.:

AF XY:

0.0000297

AC XY:

AN XY:

33670

show subpopulations

Gnomad4 AFR

AF:

0.0000979

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000188

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000264

ESP6500AA

AF:

0.000276

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Sep 01, 2016

- -

Developmental and epileptic encephalopathy, 9

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Feb 04, 2022

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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PCDH19 protein function. ClinVar contains an entry for this variant (Variation ID: 374533). This variant has not been reported in the literature in individuals affected with PCDH19-related conditions. This variant is present in population databases (rs371109150, gnomAD 0.03%). This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 992 of the PCDH19 protein (p.Ala992Val). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.50

Cadd

Benign

Dann

Benign

0.27

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.94

D;D;D

M_CAP

Pathogenic

0.48

MetaRNN

Benign

0.15

T;T;T

MetaSVM

Benign

-1.0

MutationTaster

Benign

0.98

D;D;D

PrimateAI

Uncertain

0.54

PROVEAN

Benign

0.58

N;N;N

REVEL

Benign

0.14

Sift

Benign

0.57

T;T;T

Sift4G

Benign

1.0

T;T;T

Polyphen

0.40, 0.12

.;B;B

Vest4

0.11

MVP

0.56

MPC

0.51

ClinPred

0.065

GERP RS

5.8

Varity_R

0.11

gMVP

0.39

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over