X-100408456-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_001184880.2(PCDH19):c.142G>A(p.Glu48Lys) 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. 13/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 23)
• Consequence: PCDH19 NM_001184880.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.65

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 2 ACMG points.

• PM1: In a domain Cadherin 1 (size 107) in uniprot entity PCD19_HUMAN there are 24 pathogenic changes around while only 1 benign (96%) in NM_001184880.2
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1459035).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCDH19	NM_001184880.2	c.142G>A	p.Glu48Lys	missense_variant	1/6	ENST00000373034.8
PCDH19	NM_001105243.2	c.142G>A	p.Glu48Lys	missense_variant	1/5
PCDH19	NM_020766.3	c.142G>A	p.Glu48Lys	missense_variant	1/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCDH19	ENST00000373034.8	c.142G>A	p.Glu48Lys	missense_variant	1/6	1	NM_001184880.2	A1
PCDH19	ENST00000255531.8	c.142G>A	p.Glu48Lys	missense_variant	1/5	1		P5
PCDH19	ENST00000420881.6	c.142G>A	p.Glu48Lys	missense_variant	1/5	1		A1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.78
Cadd	Benign	22
Dann	Benign	0.89
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.89	D;D;D
M_CAP	Benign	0.044	D
MetaRNN	Benign	0.15	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.41	N;N;N
MutationTaster	Benign	0.96	D;D;D
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-0.53	N;N;N
REVEL	Benign	0.054
Sift	Benign	0.45	T;T;T
Sift4G	Benign	0.79	T;T;T
Polyphen		0.010, 0.0010	.;B;B
Vest4		0.13
MutPred		0.59		Gain of MoRF binding (P = 0.0056);Gain of MoRF binding (P = 0.0056);Gain of MoRF binding (P = 0.0056);
MVP		0.32
MPC		1.3
ClinPred		0.50	D
GERP RS		5.7
Varity_R		0.29
gMVP		0.64

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: rs132630326; hg19: chrX-99663454;