X-100296360-T-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001184880.2(PCDH19):c.3364A>C(p.Met1122Leu) 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. 14/20 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 NM_001184880.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.197

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_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.053809404).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCDH19	NM_001184880.2	c.3364A>C	p.Met1122Leu	missense_variant	6/6	ENST00000373034.8
PCDH19	NM_001105243.2	c.3223A>C	p.Met1075Leu	missense_variant	5/5
PCDH19	NM_020766.3	c.3220A>C	p.Met1074Leu	missense_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCDH19	ENST00000373034.8	c.3364A>C	p.Met1122Leu	missense_variant	6/6	1	NM_001184880.2	A1
PCDH19	ENST00000255531.8	c.3223A>C	p.Met1075Leu	missense_variant	5/5	1		P5
PCDH19	ENST00000420881.6	c.3220A>C	p.Met1074Leu	missense_variant	5/5	1		A1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

Bravo AF: 0.0000151

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

Nov 24, 2022

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. 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 not expected to disrupt PCDH19 protein function. This variant has not been reported in the literature in individuals affected with PCDH19-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces methionine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1122 of the PCDH19 protein (p.Met1122Leu). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.76
Cadd	Benign	2.8
Dann	Benign	0.74
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.68	T;T;T
M_CAP	Benign	0.0092	T
MetaRNN	Benign	0.054	T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.31	N;N;N
REVEL	Benign	0.047
Sift	Benign	0.096	T;T;T
Sift4G	Benign	0.36	T;T;T
Polyphen		0.0	.;B;B
Vest4		0.22
MutPred		0.36		.;Loss of helix (P = 0.0041);.;
MVP		0.36
MPC		0.47
ClinPred		0.029	T
GERP RS		-0.27
Varity_R		0.18
gMVP		0.17

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: rs1449640534; hg19: chrX-99551358;