chrX-100407718-G-GCGGGT

Position:

• chrX-100407718-G-GCGGGT

Variant summary

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

The ENST00000373034.8(PCDH19):​c.879_880insACCCG​(p.His294ThrfsTer13) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. P293P) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 24)
• Consequence: PCDH19 ENST00000373034.8 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: -2.08

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-100407718-G-GCGGGT is Pathogenic according to our data. Variant chrX-100407718-G-GCGGGT is described in ClinVar as [Pathogenic]. Clinvar id is 504290.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCDH19	NM_001184880.2	c.879_880insACCCG	p.His294ThrfsTer13	frameshift_variant	1/6	ENST00000373034.8	NP_001171809.1
PCDH19	NM_001105243.2	c.879_880insACCCG	p.His294ThrfsTer13	frameshift_variant	1/5		NP_001098713.1
PCDH19	NM_020766.3	c.879_880insACCCG	p.His294ThrfsTer13	frameshift_variant	1/5		NP_065817.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCDH19	ENST00000373034.8	c.879_880insACCCG	p.His294ThrfsTer13	frameshift_variant	1/6	1	NM_001184880.2	ENSP00000362125	A1
PCDH19	ENST00000255531.8	c.879_880insACCCG	p.His294ThrfsTer13	frameshift_variant	1/5	1		ENSP00000255531	P5
PCDH19	ENST00000420881.6	c.879_880insACCCG	p.His294ThrfsTer13	frameshift_variant	1/5	1		ENSP00000400327	A1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 24

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Feb 02, 2018

The c.875_879dupACCCG variant in the PCDH19 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The c.875_879dupACCCG variant causes a frameshift starting with codon Histidine 294, changes this amino acid to a Threonine residue, and creates a premature Stop codon at position 13 of the new reading frame, denoted p.His294ThrfsX13. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.875_879dupACCCG variant is not observed in large population cohorts (Lek et al., 2016). We interpret c.875_879dupACCCG as a pathogenic variant. -

Developmental and epileptic encephalopathy, 9 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 28, 2018

For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in PCDH19 are known to be pathogenic (PMID: 21053371). This variant has not been reported in the literature in individuals with PCDH19-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.His294Thrfs*13) in the PCDH19 gene. It is expected to result in an absent or disrupted protein product. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1555985416; hg19: chrX-99662716;