X-100402721-G-T

Variant names:

• chrX-100402721-G-T
• rs1555984464
• NM_001184880.2:c.2419C>A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001184880.2(PCDH19):​c.2419C>A​(p.Leu807Met) variant causes a missense change. The variant allele was found at a frequency of 0.00000165 in 1,209,855 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0000089 (0 hom., 0 hem., cov: 23)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: PCDH19 NM_001184880.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.55

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.36284912).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCDH19	NM_001184880.2	c.2419C>A	p.Leu807Met	missense_variant	Exon 3 of 6	ENST00000373034.8	NP_001171809.1
PCDH19	NM_001105243.2	c.2278C>A	p.Leu760Met	missense_variant	Exon 2 of 5		NP_001098713.1
PCDH19	NM_020766.3	c.2278C>A	p.Leu760Met	missense_variant	Exon 2 of 5		NP_065817.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCDH19	ENST00000373034.8	c.2419C>A	p.Leu807Met	missense_variant	Exon 3 of 6	1	NM_001184880.2	ENSP00000362125.4
PCDH19	ENST00000255531.8	c.2278C>A	p.Leu760Met	missense_variant	Exon 2 of 5	1		ENSP00000255531.7
PCDH19	ENST00000420881.6	c.2278C>A	p.Leu760Met	missense_variant	Exon 2 of 5	1		ENSP00000400327.2
PCDH19	ENST00000636150.1	c.66-146C>A		intron_variant	Intron 1 of 2	5		ENSP00000490463.1

Frequencies

GnomAD3 genomes AF: 0.00000892 AC: 1 AN: 112131 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 34287

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000282

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 9.11e-7 AC: 1 AN: 1097724 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 363078

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000331

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000892 AC: 1 AN: 112131 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 34287

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000282

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.49
BayesDel_addAF	Uncertain	0.070	D
BayesDel_noAF	Benign	-0.14
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.027	.;T;.
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D;D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.36	T;T;T
MetaSVM	Benign	-0.44	T
MutationAssessor	Benign	0.90	.;L;.
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-0.26	N;N;N
REVEL	Benign	0.20
Sift	Uncertain	0.024	D;D;D
Sift4G	Benign	0.11	T;T;T
Polyphen		0.99, 1.0	.;D;D
Vest4		0.50
MutPred		0.40		.;Gain of sheet (P = 0.0266);.;
MVP		0.64
MPC		1.4
ClinPred		0.85	D
GERP RS		5.6
Varity_R		0.57
gMVP		0.25

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: rs1555984464; hg19: chrX-99657719;