X-100296326-C-A

Variant names:

• chrX-100296326-C-A
• NM_001184880.2:c.3398G>T

Variant summary

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

The NM_001184880.2(PCDH19):​c.3398G>T​(p.Arg1133Leu) 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. 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: 22)
• Consequence: PCDH19 NM_001184880.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.91

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=0.24967948).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCDH19	NM_001184880.2	c.3398G>T	p.Arg1133Leu	missense_variant	Exon 6 of 6	ENST00000373034.8	NP_001171809.1
PCDH19	NM_001105243.2	c.3257G>T	p.Arg1086Leu	missense_variant	Exon 5 of 5		NP_001098713.1
PCDH19	NM_020766.3	c.3254G>T	p.Arg1085Leu	missense_variant	Exon 5 of 5		NP_065817.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCDH19	ENST00000373034.8	c.3398G>T	p.Arg1133Leu	missense_variant	Exon 6 of 6	1	NM_001184880.2	ENSP00000362125.4
PCDH19	ENST00000255531.8	c.3257G>T	p.Arg1086Leu	missense_variant	Exon 5 of 5	1		ENSP00000255531.7
PCDH19	ENST00000420881.6	c.3254G>T	p.Arg1085Leu	missense_variant	Exon 5 of 5	1		ENSP00000400327.2
PCDH19	ENST00000464981.1	n.-26G>T		upstream_gene_variant		3		ENSP00000479805.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 22

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.089	.;T;.
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.90	D;D;D
M_CAP	Pathogenic	0.51	D
MetaRNN	Benign	0.25	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.97	.;L;.
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.7	N;N;N
REVEL	Benign	0.14
Sift	Uncertain	0.0040	D;D;D
Sift4G	Uncertain	0.015	D;D;D
Polyphen		0.68, 0.33	.;P;B
Vest4		0.51
MutPred		0.38		.;Gain of catalytic residue at R1133 (P = 0.0055);.;
MVP		0.46
MPC		0.67
ClinPred		0.76	D
GERP RS		2.5
Varity_R		0.27
gMVP		0.37

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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-99551324;