X-100296293-T-C

Position:

• chrX-100296293-T-C

Variant summary

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

The ENST00000373034.8(PCDH19):​c.3431A>G​(p.Lys1144Arg) 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. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K1144N) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 22)
• Consequence: PCDH19 ENST00000373034.8 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.56

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=0.21250546).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCDH19	NM_001184880.2	c.3431A>G	p.Lys1144Arg	missense_variant	6/6	ENST00000373034.8	NP_001171809.1
PCDH19	NM_001105243.2	c.3290A>G	p.Lys1097Arg	missense_variant	5/5		NP_001098713.1
PCDH19	NM_020766.3	c.3287A>G	p.Lys1096Arg	missense_variant	5/5		NP_065817.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCDH19	ENST00000373034.8	c.3431A>G	p.Lys1144Arg	missense_variant	6/6	1	NM_001184880.2	ENSP00000362125	A1
PCDH19	ENST00000255531.8	c.3290A>G	p.Lys1097Arg	missense_variant	5/5	1		ENSP00000255531	P5
PCDH19	ENST00000420881.6	c.3287A>G	p.Lys1096Arg	missense_variant	5/5	1		ENSP00000400327	A1
PCDH19	ENST00000464981.1	c.8A>G	p.Lys3Arg	missense_variant, NMD_transcript_variant	1/2	3		ENSP00000479805

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 22

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jan 21, 2020

Not observed in large population cohorts (Lek et al., 2016); The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.039	.;T;.
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.87	D;D;D
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.21	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.63	.;N;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-0.59	N;N;N
REVEL	Benign	0.072
Sift	Benign	0.052	T;D;T
Sift4G	Benign	0.27	T;T;T
Polyphen		0.0090, 0.015	.;B;B
Vest4		0.18
MutPred		0.19		.;Loss of helix (P = 0.0196);.;
MVP		0.69
MPC		0.41
ClinPred		0.48	T
GERP RS		5.5
Varity_R		0.26
gMVP		0.42

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-99551291;