rs757949591

chrX-100350664-C-T

Variant summary

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

The NM_001184880.2(PCDH19):c.2657G>A(p.Arg886Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000186 in 1,075,807 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 0.0000019 (0 hom. 1 hem.)
• Consequence: PCDH19 NM_001184880.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.91

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	UniProt
PCDH19	NM_001184880.2	c.2657G>A	p.Arg886Gln	missense_variant	4/6	ENST00000373034.8
PCDH19	NM_001105243.2	c.2516G>A	p.Arg839Gln	missense_variant	3/5
PCDH19	NM_020766.3	c.2516G>A	p.Arg839Gln	missense_variant	3/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCDH19	ENST00000373034.8	c.2657G>A	p.Arg886Gln	missense_variant	4/6	1	NM_001184880.2	A1
PCDH19	ENST00000255531.8	c.2516G>A	p.Arg839Gln	missense_variant	3/5	1		P5
PCDH19	ENST00000420881.6	c.2516G>A	p.Arg839Gln	missense_variant	3/5	1		A1
PCDH19	ENST00000636150.1	c.158G>A	p.Arg53Gln	missense_variant	3/3	5

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD3 exomes AF: 0.0000111 AC: 2 AN: 179913 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 65837

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000743

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000124

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000186 AC: 2 AN: 1075807 Hom.: 0 Cov.: 25 AF XY: 0.00000291 AC XY: 1 AN XY: 343881

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000332

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000247

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 24

Bravo AF: 0.0000189

ExAC AF: 0.0000166 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Developmental and epileptic encephalopathy, 9 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 14, 2023

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 886 of the PCDH19 protein (p.Arg886Gln). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with PCDH19-related conditions. ClinVar contains an entry for this variant (Variation ID: 579743). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PCDH19 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
Cadd	Pathogenic	28
Dann	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;D;D;D
M_CAP	Pathogenic	0.83	D
MetaRNN	Uncertain	0.46	T;T;T;D
MetaSVM	Benign	-0.66	T
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-1.2	N;N;N;.
REVEL	Benign	0.28
Sift	Uncertain	0.0050	D;D;T;.
Sift4G	Uncertain	0.051	T;D;D;.
Polyphen		1.0, 1.0	.;D;D;.
Vest4		0.78
MutPred		0.63		.;Loss of sheet (P = 0.0315);.;.;
MVP		0.79
MPC		1.5
ClinPred		0.72	D
GERP RS		5.5
Varity_R		0.62
gMVP		0.63

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: rs757949591; hg19: chrX-99605662; COSMIC: COSV55267948;