X-100296340-A-C

Position:

• chrX-100296340-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000373034.8(PCDH19):​c.3384T>G​(p.Ile1128Met) 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 benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: PCDH19 ENST00000373034.8 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.638

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1073699).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCDH19	NM_001184880.2	c.3384T>G	p.Ile1128Met	missense_variant	6/6	ENST00000373034.8	NP_001171809.1
PCDH19	NM_001105243.2	c.3243T>G	p.Ile1081Met	missense_variant	5/5		NP_001098713.1
PCDH19	NM_020766.3	c.3240T>G	p.Ile1080Met	missense_variant	5/5		NP_065817.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCDH19	ENST00000373034.8	c.3384T>G	p.Ile1128Met	missense_variant	6/6	1	NM_001184880.2	ENSP00000362125	A1
PCDH19	ENST00000255531.8	c.3243T>G	p.Ile1081Met	missense_variant	5/5	1		ENSP00000255531	P5
PCDH19	ENST00000420881.6	c.3240T>G	p.Ile1080Met	missense_variant	5/5	1		ENSP00000400327	A1
PCDH19	ENST00000464981.1			upstream_gene_variant		3		ENSP00000479805

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

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

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2020

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 are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with PCDH19-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces isoleucine with methionine at codon 1128 of the PCDH19 protein (p.Ile1128Met). The isoleucine residue is moderately conserved and there is a small physicochemical difference between isoleucine and methionine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	21
DANN	Benign	0.96
DEOGEN2	Benign	0.028	.;T;.
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.82	T;T;T
M_CAP	Benign	0.046	D
MetaRNN	Benign	0.11	T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.34	.;N;.
MutationTaster	Benign	0.51	N;N;N
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.12	N;N;N
REVEL	Benign	0.11
Sift	Uncertain	0.0080	D;D;D
Sift4G	Uncertain	0.016	D;D;D
Polyphen		0.010, 0.14	.;B;B
Vest4		0.26
MutPred		0.13		.;Gain of sheet (P = 0.0166);.;
MVP		0.62
MPC		0.54
ClinPred		0.31	T
GERP RS		4.1
Varity_R		0.26
gMVP		0.088

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: rs1924600376; hg19: chrX-99551338; COSMIC: COSV55257990; COSMIC: COSV55257990;