rs132630323

Positions:

• chrX-100407276-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The ENST00000373034.8(PCDH19):​c.1322T>A​(p.Val441Glu) variant causes a missense change involving the alteration of a 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 Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V441L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 24)
• Consequence: PCDH19 ENST00000373034.8 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.32

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 9 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 5 uncertain in ENST00000373034.8
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.992
• PP5: Variant X-100407276-A-T is Pathogenic according to our data. Variant chrX-100407276-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 11016.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chrX-100407276-A-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCDH19	NM_001184880.2	c.1322T>A	p.Val441Glu	missense_variant	1/6	ENST00000373034.8	NP_001171809.1
PCDH19	NM_001105243.2	c.1322T>A	p.Val441Glu	missense_variant	1/5		NP_001098713.1
PCDH19	NM_020766.3	c.1322T>A	p.Val441Glu	missense_variant	1/5		NP_065817.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCDH19	ENST00000373034.8	c.1322T>A	p.Val441Glu	missense_variant	1/6	1	NM_001184880.2	ENSP00000362125	A1
PCDH19	ENST00000255531.8	c.1322T>A	p.Val441Glu	missense_variant	1/5	1		ENSP00000255531	P5
PCDH19	ENST00000420881.6	c.1322T>A	p.Val441Glu	missense_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:1

Revision: no assertion criteria provided

Submissions by phenotype

Developmental and epileptic encephalopathy, 9 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 01, 2008

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.49
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.46	.;T;.
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D;D;D
M_CAP	Pathogenic	0.93	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Uncertain	0.67	D
MutationAssessor	Pathogenic	4.4	H;H;H
MutationTaster	Benign	1.0	A;A;A
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-5.5	D;D;D
REVEL	Pathogenic	0.88
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		1.0	.;D;D
Vest4		0.96
MutPred		0.90		Gain of disorder (P = 0.0087);Gain of disorder (P = 0.0087);Gain of disorder (P = 0.0087);
MVP		0.98
MPC		1.8
ClinPred		1.0	D
GERP RS		6.0
Varity_R		0.98
gMVP		0.93

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: rs132630323; hg19: chrX-99662274;