rs866113078

Positions:

• chrX-100407702-G-A

Variant summary

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

The NM_001184880.2(PCDH19):​c.896C>T​(p.Thr299Ile) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 25)
• Consequence: PCDH19 NM_001184880.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.85

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.896C>T	p.Thr299Ile	missense_variant	1/6	ENST00000373034.8	NP_001171809.1
PCDH19	NM_001105243.2	c.896C>T	p.Thr299Ile	missense_variant	1/5		NP_001098713.1
PCDH19	NM_020766.3	c.896C>T	p.Thr299Ile	missense_variant	1/5		NP_065817.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCDH19	ENST00000373034.8	c.896C>T	p.Thr299Ile	missense_variant	1/6	1	NM_001184880.2	ENSP00000362125.4
PCDH19	ENST00000255531.8	c.896C>T	p.Thr299Ile	missense_variant	1/5	1		ENSP00000255531.7
PCDH19	ENST00000420881.6	c.896C>T	p.Thr299Ile	missense_variant	1/5	1		ENSP00000400327.2

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD3 exomes AF: 0.0000110 AC: 2 AN: 181640 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 67510

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000246

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 25

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

Athena Diagnostics

Sep 22, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Uncertain	0.015	T
BayesDel_noAF	Benign	-0.16
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.23	.;T;.
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.79	T;T;T
M_CAP	Uncertain	0.14	D
MetaRNN	Uncertain	0.51	D;D;D
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	1.9	L;L;L
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-3.0	D;D;D
REVEL	Benign	0.19
Sift	Benign	0.054	T;T;T
Sift4G	Benign	0.096	T;T;T
Polyphen		0.99, 0.58	.;D;P
Vest4		0.63
MutPred		0.50		Gain of catalytic residue at L304 (P = 0.0797);Gain of catalytic residue at L304 (P = 0.0797);Gain of catalytic residue at L304 (P = 0.0797);
MVP		0.58
MPC		2.1
ClinPred		0.76	D
GERP RS		6.0
Varity_R		0.74
gMVP		0.78

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: rs866113078; hg19: chrX-99662700;