X-100407263-G-T

Variant names:

• chrX-100407263-G-T
• rs796052815
• NM_001184880.2:c.1335C>A

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM1 PM2 PP2 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 (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• 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
• Publications: 2 publications found

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 Gene-Disease associations (from GenCC):

• developmental and epileptic encephalopathy, 9

  Inheritance: XL, Unknown Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics
• X-linked complex neurodevelopmental disorder

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
• Dravet syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 9 uncertain in NM_001184880.2
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 107 curated pathogenic missense variants (we use a threshold of 10). The gene has 20 curated benign missense variants. Gene score misZ: 2.5929 (below the threshold of 3.09). Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to Dravet syndrome, developmental and epileptic encephalopathy, 9, X-linked complex neurodevelopmental disorder.
• 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 VariationId is 206331.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

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

Ensembl

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

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 24

Alfa AF: 0.00 Hom.: 0

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

Dec 20, 2019

Neurogenetics Research Program, University of Adelaide

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

not provided Pathogenic:1

Mar 15, 2013

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
PhyloP100		-0.96
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
Mutation Taster		=2/98	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs796052815; hg19: chrX-99662261;