X-100408507-C-T

Position:

• chrX-100408507-C-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.91G>A​(p.Glu31Lys) variant causes a missense change. 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 Pathogenic (★).

• Frequency: Genomes: not found (cov: 24)
• Consequence: PCDH19 NM_001184880.2 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 6.02

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, 0.976
• PP5: Variant X-100408507-C-T is Pathogenic according to our data. Variant chrX-100408507-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 578043.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.91G>A	p.Glu31Lys	missense_variant	1/6	ENST00000373034.8	NP_001171809.1
PCDH19	NM_001105243.2	c.91G>A	p.Glu31Lys	missense_variant	1/5		NP_001098713.1
PCDH19	NM_020766.3	c.91G>A	p.Glu31Lys	missense_variant	1/5		NP_065817.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCDH19	ENST00000373034.8	c.91G>A	p.Glu31Lys	missense_variant	1/6	1	NM_001184880.2	ENSP00000362125.4
PCDH19	ENST00000255531.8	c.91G>A	p.Glu31Lys	missense_variant	1/5	1		ENSP00000255531.7
PCDH19	ENST00000420881.6	c.91G>A	p.Glu31Lys	missense_variant	1/5	1		ENSP00000400327.2

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 24

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Developmental and epileptic encephalopathy, 9 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 22, 2022

For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PCDH19 protein function. ClinVar contains an entry for this variant (Variation ID: 578043). This missense change has been observed in individual(s) with clinical features of developmental and epileptic encephalopathy (PMID: 23334464). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 31 of the PCDH19 protein (p.Glu31Lys). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.38	.;T;.
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Pathogenic	0.82	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Uncertain	0.36	D
MutationAssessor	Pathogenic	4.3	H;H;H
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-3.6	D;D;D
REVEL	Uncertain	0.62
Sift	Pathogenic	0.0	D;D;D
Sift4G	Uncertain	0.0040	D;D;D
Polyphen		1.0	.;D;D
Vest4		0.63
MutPred		0.91		Gain of methylation at E31 (P = 0.0166);Gain of methylation at E31 (P = 0.0166);Gain of methylation at E31 (P = 0.0166);
MVP		0.96
MPC		2.5
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.98
gMVP		1.0

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: rs796052794; hg19: chrX-99663505;