rs370078729

Positions:

• chrX-100296462-C-G
• chrX-100296462-C-T

Variant summary

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

The NM_001184880.2(PCDH19):​c.3262G>C​(p.Ala1088Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000911 in 1,098,147 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. 12/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: PCDH19 NM_001184880.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.26

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.3262G>C	p.Ala1088Pro	missense_variant	6/6	ENST00000373034.8	NP_001171809.1
PCDH19	NM_001105243.2	c.3121G>C	p.Ala1041Pro	missense_variant	5/5		NP_001098713.1
PCDH19	NM_020766.3	c.3118G>C	p.Ala1040Pro	missense_variant	5/5		NP_065817.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCDH19	ENST00000373034.8	c.3262G>C	p.Ala1088Pro	missense_variant	6/6	1	NM_001184880.2	ENSP00000362125.4
PCDH19	ENST00000255531.8	c.3121G>C	p.Ala1041Pro	missense_variant	5/5	1		ENSP00000255531.7
PCDH19	ENST00000420881.6	c.3118G>C	p.Ala1040Pro	missense_variant	5/5	1		ENSP00000400327.2

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD3 exomes AF: 0.00000551 AC: 1 AN: 181434 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 67416

Gnomad AFR exome AF: 0.0000807

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 9.11e-7 AC: 1 AN: 1098147 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 363505

Gnomad4 AFR exome AF: 0.0000379

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

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 Cov.: 22

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.037	.;T;.
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.83	T;T;T
M_CAP	Pathogenic	0.54	D
MetaRNN	Uncertain	0.52	D;D;D
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	0.34	.;N;.
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-0.55	N;N;N
REVEL	Benign	0.17
Sift	Uncertain	0.018	D;D;D
Sift4G	Benign	0.12	T;T;T
Polyphen		0.26, 0.51	.;B;P
Vest4		0.53
MutPred		0.41		.;Gain of sheet (P = 0.0043);.;
MVP		0.66
MPC		0.65
ClinPred		0.14	T
GERP RS		4.1
Varity_R		0.26
gMVP		0.38

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: rs370078729; hg19: chrX-99551460;