X-100407263-G-T

Position:

• chrX-100407263-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_Moderate

The NM_001184880.2(PCDH19):​c.1335C>A​(p.Asp445Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 24)
• Consequence: PCDH19 NM_001184880.2 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: -0.957

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 Likely_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.983
• PP5: Variant X-100407263-G-T is Pathogenic according to our data. Variant chrX-100407263-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 206331.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCDH19	NM_001184880.2	c.1335C>A	p.Asp445Glu	missense_variant	1/6	ENST00000373034.8	NP_001171809.1
PCDH19	NM_001105243.2	c.1335C>A	p.Asp445Glu	missense_variant	1/5		NP_001098713.1
PCDH19	NM_020766.3	c.1335C>A	p.Asp445Glu	missense_variant	1/5		NP_065817.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCDH19	ENST00000373034.8	c.1335C>A	p.Asp445Glu	missense_variant	1/6	1	NM_001184880.2	ENSP00000362125.4
PCDH19	ENST00000255531.8	c.1335C>A	p.Asp445Glu	missense_variant	1/5	1		ENSP00000255531.7
PCDH19	ENST00000420881.6	c.1335C>A	p.Asp445Glu	missense_variant	1/5	1		ENSP00000400327.2

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 24

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Glycine encephalopathy;C1848137:Developmental and epileptic encephalopathy, 9 Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

Neurogenetics Research Program, University of Adelaide

Dec 20, 2019

- -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 15, 2013

This variant is denoted p.Asp445Glu (GAC>GAA): c.1335 C>A in exon 1 of the PCDH19 gene (NM_001105243.1). The Asp445Glu missense change has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. It was not observed in approximately 6,300 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project or among the various ethnic groups studied in the 1000 Genomes Project, indicating it is not a common benign variant in these populations. The amino acid substitution is conservative as both Aspartic acid and Glutamic acid are negatively charged, polar amino acid residues. However, Asp445Glu alters a highly conserved position in the fourth extracellular cadherin repeat domain of the protein and other missense mutations in this domain have been published in association with epilepsy (Dibbens et al., 2008; Specchio et al., 2011). In addition, multiple in-silico algorithms predict Asp445Glu may be damaging to the structure/function of the protein. Therefore, based on the currently available information, Asp445Glu is a strong candidate for a disease-causing mutation, although the possibility that it is a benign variant cannot be excluded. The variant is found in EPILEPSY panel(s). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.40
CADD	Benign	9.5
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.55	.;D;.
FATHMM_MKL	Benign	0.44	N
LIST_S2	Uncertain	0.93	D;D;D
M_CAP	Pathogenic	0.71	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Uncertain	0.63	D
MutationAssessor	Pathogenic	3.9	H;H;H
PrimateAI	Uncertain	0.79	T
PROVEAN	Uncertain	-3.7	D;D;D
REVEL	Pathogenic	0.72
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0, 1.0	.;D;D
Vest4		0.92
MutPred		0.90		Gain of catalytic residue at D445 (P = 0.1348);Gain of catalytic residue at D445 (P = 0.1348);Gain of catalytic residue at D445 (P = 0.1348);
MVP		1.0
MPC		1.4
ClinPred		1.0	D
GERP RS		-4.6
Varity_R		0.97
gMVP		0.78

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: rs796052815; hg19: chrX-99662261;