X-100296354-C-T

Variant names:

• chrX-100296354-C-T
• NM_001184880.2:c.3370G>A

Variant summary

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

The NM_001184880.2(PCDH19):​c.3370G>A​(p.Glu1124Lys) 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: 7.24

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 rank	MANE	Protein	UniProt
PCDH19	NM_001184880.2	c.3370G>A	p.Glu1124Lys	missense_variant	Exon 6 of 6	ENST00000373034.8	NP_001171809.1
PCDH19	NM_001105243.2	c.3229G>A	p.Glu1077Lys	missense_variant	Exon 5 of 5		NP_001098713.1
PCDH19	NM_020766.3	c.3226G>A	p.Glu1076Lys	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.3370G>A	p.Glu1124Lys	missense_variant	Exon 6 of 6	1	NM_001184880.2	ENSP00000362125.4
PCDH19	ENST00000255531.8	c.3229G>A	p.Glu1077Lys	missense_variant	Exon 5 of 5	1		ENSP00000255531.7
PCDH19	ENST00000420881.6	c.3226G>A	p.Glu1076Lys	missense_variant	Exon 5 of 5	1		ENSP00000400327.2
PCDH19	ENST00000464981.1	n.-54G>A		upstream_gene_variant		3		ENSP00000479805.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.064	.;T;.
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.91	D;D;D
M_CAP	Pathogenic	0.64	D
MetaRNN	Uncertain	0.45	T;T;T
MetaSVM	Benign	-0.46	T
MutationAssessor	Benign	1.0	.;L;.
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-0.76	N;N;N
REVEL	Benign	0.29
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		0.99, 1.0	.;D;D
Vest4		0.47
MutPred		0.36		.;Gain of MoRF binding (P = 0.0037);.;
MVP		0.89
MPC		0.81
ClinPred		0.88	D
GERP RS		5.5
Varity_R		0.81
gMVP		0.49

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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-99551352;