X-100296357-G-A

Position:

• chrX-100296357-G-A

Variant summary

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

The NM_001184880.2(PCDH19):​c.3367C>T​(p.His1123Tyr) 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: PCDH19 NM_001184880.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.95

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=0.19376355).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCDH19	NM_001184880.2	c.3367C>T	p.His1123Tyr	missense_variant	6/6	ENST00000373034.8	NP_001171809.1
PCDH19	NM_001105243.2	c.3226C>T	p.His1076Tyr	missense_variant	5/5		NP_001098713.1
PCDH19	NM_020766.3	c.3223C>T	p.His1075Tyr	missense_variant	5/5		NP_065817.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCDH19	ENST00000373034.8	c.3367C>T	p.His1123Tyr	missense_variant	6/6	1	NM_001184880.2	ENSP00000362125	A1
PCDH19	ENST00000255531.8	c.3226C>T	p.His1076Tyr	missense_variant	5/5	1		ENSP00000255531	P5
PCDH19	ENST00000420881.6	c.3223C>T	p.His1075Tyr	missense_variant	5/5	1		ENSP00000400327	A1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 22

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Dec 20, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.038	.;T;.
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.74	T;T;T
M_CAP	Pathogenic	0.33	D
MetaRNN	Benign	0.19	T;T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.55	.;N;.
MutationTaster	Benign	0.59	D;D;N
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.0	N;N;N
REVEL	Benign	0.030
Sift	Uncertain	0.023	D;D;D
Sift4G	Benign	0.082	T;T;T
Polyphen		0.52, 0.10	.;P;B
Vest4		0.24
MutPred		0.32		.;Gain of sheet (P = 0.0016);.;
MVP		0.50
MPC		0.59
ClinPred		0.49	T
GERP RS		4.7
Varity_R		0.29
gMVP		0.13

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-99551355;