rs1555985491

chrX-100407907-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_001184880.2(PCDH19):c.691T>G(p.Ser231Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 24)
• Consequence: PCDH19 NM_001184880.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U: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 Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_001184880.2
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCDH19	NM_001184880.2	c.691T>G	p.Ser231Ala	missense_variant	1/6	ENST00000373034.8
PCDH19	NM_001105243.2	c.691T>G	p.Ser231Ala	missense_variant	1/5
PCDH19	NM_020766.3	c.691T>G	p.Ser231Ala	missense_variant	1/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCDH19	ENST00000373034.8	c.691T>G	p.Ser231Ala	missense_variant	1/6	1	NM_001184880.2	A1
PCDH19	ENST00000255531.8	c.691T>G	p.Ser231Ala	missense_variant	1/5	1		P5
PCDH19	ENST00000420881.6	c.691T>G	p.Ser231Ala	missense_variant	1/5	1		A1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 24

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

Invitae

Oct 31, 2017

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with PCDH19-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces serine with alanine at codon 231 of the PCDH19 protein (p.Ser231Ala). The serine residue is highly conserved and there is a moderate physicochemical difference between serine and alanine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.022	T
BayesDel_noAF	Benign	-0.27
Cadd	Uncertain	25
Dann	Uncertain	0.99
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.77	T;T;T
M_CAP	Uncertain	0.16	D
MetaRNN	Uncertain	0.46	T;T;T
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	-0.64	N;N;N
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-1.1	N;N;N
REVEL	Uncertain	0.31
Sift	Benign	0.057	T;T;T
Sift4G	Uncertain	0.020	D;D;D
Polyphen		0.98, 1.0	.;D;D
Vest4		0.66
MutPred		0.28		Loss of disorder (P = 0.0452);Loss of disorder (P = 0.0452);Loss of disorder (P = 0.0452);
MVP		0.89
MPC		2.2
ClinPred		0.93	D
GERP RS		6.1
Varity_R		0.69
gMVP		0.48

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: rs1555985491; hg19: chrX-99662905;