rs756414485

Positions:

• chrX-100350665-G-A
• chrX-100350665-G-C

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.2656C>T​(p.Arg886Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.000000929 in 1,076,197 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 9.3e-7 (0 hom. 0 hem.)
• Consequence: PCDH19 NM_001184880.2 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 4.89

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-100350665-G-A is Pathogenic according to our data. Variant chrX-100350665-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 206341.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-100350665-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCDH19	NM_001184880.2	c.2656C>T	p.Arg886Ter	stop_gained	4/6	ENST00000373034.8
PCDH19	NM_001105243.2	c.2515C>T	p.Arg839Ter	stop_gained	3/5
PCDH19	NM_020766.3	c.2515C>T	p.Arg839Ter	stop_gained	3/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCDH19	ENST00000373034.8	c.2656C>T	p.Arg886Ter	stop_gained	4/6	1	NM_001184880.2	A1
PCDH19	ENST00000255531.8	c.2515C>T	p.Arg839Ter	stop_gained	3/5	1		P5
PCDH19	ENST00000420881.6	c.2515C>T	p.Arg839Ter	stop_gained	3/5	1		A1
PCDH19	ENST00000636150.1	c.157C>T	p.Arg53Ter	stop_gained	3/3	5

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome AF: 9.29e-7 AC: 1 AN: 1076197 Hom.: 0 Cov.: 25 AF XY: 0.00 AC XY: 0 AN XY: 344305

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000122

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 24

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 14, 2019	Previously reported to segregate with epilepsy in several females from a single family who had febrile, generalized, and/or focal seizures, one of whom also had cognitive delay (Depienne et al., 2011); Nonsense 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 in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 23334464, 22267240, 25525159, 21053371, 27179713, 23712037, 22633638, 29377098) -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 16, 2017	- -

Developmental and epileptic encephalopathy, 9 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 16, 2024	This sequence change creates a premature translational stop signal (p.Arg886*) in the PCDH19 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PCDH19 are known to be pathogenic (PMID: 21053371). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with generalized epilepsy with febrile seizures plus (PMID: 21053371). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 206341). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 25, 2024	- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 14, 2019

The p.R886* pathogenic mutation (also known as c.2656C>T), located in coding exon 4 of the PCDH19 gene, results from a C to T substitution at nucleotide position 2656. This changes the amino acid from an arginine to a stop codon within coding exon 4. This variant has been reported in 5 females with seizures, including one family with 4 affected women (Depienne C et al. Hum. Mutat., 2011 Jan;32:E1959-75; Smith L et al. Epilepsia, 2018 03;59:679-689). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.65	D
BayesDel_noAF	Pathogenic	0.63
CADD	Pathogenic	37
DANN	Uncertain	1.0
FATHMM_MKL	Uncertain	0.94	D
MutationTaster	Benign	1.0	A;A;A
Vest4		0.85
GERP RS		5.5

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

Other links and lift over

dbSNP: rs756414485; hg19: chrX-99605663;