rs1060502175

Positions:

• chrX-100402798-AT-A
• chrX-100402798-AT-ATT

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001184880.2(PCDH19):​c.2341delA​(p.Ile781fs) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 23)
• Consequence: PCDH19 NM_001184880.2 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 4.57

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-100402798-AT-A is Pathogenic according to our data. Variant chrX-100402798-AT-A is described in ClinVar as [Pathogenic]. Clinvar id is 408902.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-100402798-AT-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCDH19	NM_001184880.2	c.2341delA	p.Ile781fs	frameshift_variant	3/6	ENST00000373034.8	NP_001171809.1
PCDH19	NM_001105243.2	c.2200delA	p.Ile734fs	frameshift_variant	2/5		NP_001098713.1
PCDH19	NM_020766.3	c.2200delA	p.Ile734fs	frameshift_variant	2/5		NP_065817.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCDH19	ENST00000373034.8	c.2341delA	p.Ile781fs	frameshift_variant	3/6	1	NM_001184880.2	ENSP00000362125.4
PCDH19	ENST00000255531.8	c.2200delA	p.Ile734fs	frameshift_variant	2/5	1		ENSP00000255531.7
PCDH19	ENST00000420881.6	c.2200delA	p.Ile734fs	frameshift_variant	2/5	1		ENSP00000400327.2
PCDH19	ENST00000636150.1	c.66-224delA		intron_variant		5		ENSP00000490463.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Developmental and epileptic encephalopathy, 9 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Mar 06, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 20, 2016	This sequence change deletes 1 nucleotide from exon 3 of the PCDH19 mRNA (c.2341delA), causing a frameshift at codon 781. This creates a premature translational stop signal (p.Ile781Serfs*19) and is expected to result in an absent or disrupted protein product. While this particular variant has not been reported in the literature, truncating variants in PCDH19 are known to be pathogenic (PMID: 21053371). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Apr 18, 2023

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 21053371, 30287595, 34055682) -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs1060502175; hg19: chrX-99657796;