rs587784296

chrX-100406629-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_001184880.2(PCDH19):c.1969C>T(p.Leu657Phe) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. L657L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 23)
• Consequence: PCDH19 NM_001184880.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.86

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 Uncertain_significance. Variant got 3 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_001184880.2
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2786317).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCDH19	NM_001184880.2	c.1969C>T	p.Leu657Phe	missense_variant	1/6	ENST00000373034.8
PCDH19	NM_001105243.2	c.1969C>T	p.Leu657Phe	missense_variant	1/5
PCDH19	NM_020766.3	c.1969C>T	p.Leu657Phe	missense_variant	1/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCDH19	ENST00000373034.8	c.1969C>T	p.Leu657Phe	missense_variant	1/6	1	NM_001184880.2	A1
PCDH19	ENST00000255531.8	c.1969C>T	p.Leu657Phe	missense_variant	1/5	1		P5
PCDH19	ENST00000420881.6	c.1969C>T	p.Leu657Phe	missense_variant	1/5	1		A1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Developmental and epileptic encephalopathy, 9 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Feb 04, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
Cadd	Benign	23
Dann	Benign	0.66
FATHMM_MKL	Benign	0.76	D
LIST_S2	Uncertain	0.86	D;D;D
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.28	T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.86	L;L;L
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-1.2	N;N;N
REVEL	Benign	0.14
Sift	Benign	0.17	T;T;T
Sift4G	Benign	0.42	T;T;T
Polyphen		0.85, 0.082	.;P;B
Vest4		0.21
MutPred		0.57		Loss of stability (P = 0.2024);Loss of stability (P = 0.2024);Loss of stability (P = 0.2024);
MVP		0.63
MPC		1.1
ClinPred		0.56	D
GERP RS		5.0
Varity_R		0.19
gMVP		0.77

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: rs587784296; hg19: chrX-99661627;