X-100406898-G-T

Position:

• chrX-100406898-G-T

Variant summary

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

The NM_001184880.2(PCDH19):​c.1700C>A​(p.Pro567His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: 8.14

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.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCDH19	NM_001184880.2	c.1700C>A	p.Pro567His	missense_variant	1/6	ENST00000373034.8	NP_001171809.1
PCDH19	NM_001105243.2	c.1700C>A	p.Pro567His	missense_variant	1/5		NP_001098713.1
PCDH19	NM_020766.3	c.1700C>A	p.Pro567His	missense_variant	1/5		NP_065817.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCDH19	ENST00000373034.8	c.1700C>A	p.Pro567His	missense_variant	1/6	1	NM_001184880.2	ENSP00000362125.4
PCDH19	ENST00000255531.8	c.1700C>A	p.Pro567His	missense_variant	1/5	1		ENSP00000255531.7
PCDH19	ENST00000420881.6	c.1700C>A	p.Pro567His	missense_variant	1/5	1		ENSP00000400327.2

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	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.070
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.20	.;T;.
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D;D;D
M_CAP	Uncertain	0.17	D
MetaRNN	Uncertain	0.43	T;T;T
MetaSVM	Benign	-0.64	T
MutationAssessor	Benign	1.1	L;L;L
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-2.3	N;N;N
REVEL	Uncertain	0.32
Sift	Uncertain	0.016	D;D;D
Sift4G	Uncertain	0.039	D;D;D
Polyphen		1.0, 1.0	.;D;D
Vest4		0.62
MutPred		0.34		Loss of catalytic residue at P566 (P = 0.0176);Loss of catalytic residue at P566 (P = 0.0176);Loss of catalytic residue at P566 (P = 0.0176);
MVP		0.55
MPC		1.5
ClinPred		0.95	D
GERP RS		5.8
Varity_R		0.44
gMVP		0.65

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: rs201989363; hg19: chrX-99661896;