rs374593325

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001184880.2(PCDH19):c.1618C>T(p.Leu540Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00035 in 1,210,262 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 241 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. L540L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00023 ( 0 hom., 19 hem., cov: 24)

Exomes 𝑓: 0.00036 ( 0 hom. 222 hem. )

Consequence

PCDH19
NM_001184880.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.313

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 Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.01000607).

BP6

Variant X-100406980-G-A is Benign according to our data. Variant chrX-100406980-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 206334.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-100406980-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000232 (26/112053) while in subpopulation SAS AF= 0.00986 (26/2638). AF 95% confidence interval is 0.00691. There are 0 homozygotes in gnomad4. There are 19 alleles in male gnomad4 subpopulation. This position pass quality control queck.

BS2

High Hemizygotes in GnomAd at 19 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
PCDH19	NM_001184880.2 linkuse as main transcript	c.1618C>T	p.Leu540Phe	missense_variant	1/6	ENST00000373034.8
PCDH19	NM_001105243.2 linkuse as main transcript	c.1618C>T	p.Leu540Phe	missense_variant	1/5
PCDH19	NM_020766.3 linkuse as main transcript	c.1618C>T	p.Leu540Phe	missense_variant	1/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCDH19	ENST00000373034.8 linkuse as main transcript	c.1618C>T	p.Leu540Phe	missense_variant	1/6	1	NM_001184880.2	A1	Q8TAB3-1
PCDH19	ENST00000255531.8 linkuse as main transcript	c.1618C>T	p.Leu540Phe	missense_variant	1/5	1		P5	Q8TAB3-2
PCDH19	ENST00000420881.6 linkuse as main transcript	c.1618C>T	p.Leu540Phe	missense_variant	1/5	1		A1	Q8TAB3-3

Frequencies

GnomAD3 genomes

AF:

0.000241

AC:

AN:

111998

Hom.:

Cov.:

AF XY:

0.000557

AC XY:

AN XY:

34138

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:

0.0102

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000666

AC:

121

AN:

181793

Hom.:

AF XY:

0.00114

AC XY:

AN XY:

67589

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000365

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00603

Gnomad FIN exome

AF:

0.0000630

Gnomad NFE exome

AF:

0.0000368

Gnomad OTH exome

AF:

0.000224

GnomAD4 exome

AF:

0.000361

AC:

397

AN:

1098209

Hom.:

Cov.:

AF XY:

0.000611

AC XY:

222

AN XY:

363567

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000284

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00615

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000499

Gnomad4 OTH exome

AF:

0.000434

GnomAD4 genome

AF:

0.000232

AC:

AN:

112053

Hom.:

Cov.:

AF XY:

0.000556

AC XY:

AN XY:

34203

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00986

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000189

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.000990

AC:

120

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 27, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Feb 09, 2017	- -

Developmental and epileptic encephalopathy, 9

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 01, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.78

BayesDel_noAF

Benign

-0.89

Cadd

Benign

Dann

Uncertain

0.99

FATHMM_MKL

Uncertain

0.82

LIST_S2

Uncertain

0.87

D;D;D

M_CAP

Benign

0.011

MetaRNN

Benign

0.010

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.20

N;N;N

MutationTaster

Benign

0.77

N;N;N

PrimateAI

Uncertain

0.50

PROVEAN

Benign

1.1

N;N;N

REVEL

Benign

0.050

Sift

Benign

0.10

T;T;T

Sift4G

Uncertain

0.021

D;D;D

Polyphen

0.25, 0.71

.;B;P

Vest4

0.19

MutPred

0.39

Loss of ubiquitination at K536 (P = 0.0578);Loss of ubiquitination at K536 (P = 0.0578);Loss of ubiquitination at K536 (P = 0.0578);

MVP

0.22

MPC

0.65

ClinPred

0.026

GERP RS

1.6

Varity_R

0.094

gMVP

0.23

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