rs1452944576

Positions:

• chrX-100403557-T-C
• chrX-100403557-T-G

Variant summary

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

The NM_001184880.2(PCDH19):​c.2255A>G​(p.Lys752Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000182 in 1,096,142 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000018 (0 hom. 1 hem.)
• Consequence: PCDH19 NM_001184880.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.34

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=0.10549474).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCDH19	NM_001184880.2	c.2255A>G	p.Lys752Arg	missense_variant	2/6	ENST00000373034.8	NP_001171809.1
PCDH19	NM_001105243.2	c.2148-706A>G		intron_variant			NP_001098713.1
PCDH19	NM_020766.3	c.2148-706A>G		intron_variant			NP_065817.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCDH19	ENST00000373034.8	c.2255A>G	p.Lys752Arg	missense_variant	2/6	1	NM_001184880.2	ENSP00000362125.4
PCDH19	ENST00000255531.8	c.2148-706A>G		intron_variant		1		ENSP00000255531.7
PCDH19	ENST00000420881.6	c.2148-706A>G		intron_variant		1		ENSP00000400327.2
PCDH19	ENST00000636150.1	c.66-982A>G		intron_variant		5		ENSP00000490463.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD3 exomes AF: 0.00000574 AC: 1 AN: 174306 Hom.: 0 AF XY: 0.0000153 AC XY: 1 AN XY: 65478

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000368

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: 0.00000182 AC: 2 AN: 1096142 Hom.: 0 Cov.: 31 AF XY: 0.00000276 AC XY: 1 AN XY: 362316

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000568

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.: 23

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 06, 2021

The c.2255A>G (p.K752R) alteration is located in exon 2 (coding exon 2) of the PCDH19 gene. This alteration results from a A to G substitution at nucleotide position 2255, causing the lysine (K) at amino acid position 752 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Developmental and epileptic encephalopathy, 9 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 27, 2023

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) performed at Invitae indicates that this missense variant is not expected to disrupt PCDH19 protein function. ClinVar contains an entry for this variant (Variation ID: 465298). This variant has not been reported in the literature in individuals affected with PCDH19-related conditions. 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 sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 752 of the PCDH19 protein (p.Lys752Arg). 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	0.085
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	19
DANN	Benign	0.97
DEOGEN2	Benign	0.025	T
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.60	T
M_CAP	Benign	0.042	D
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.39	N
REVEL	Benign	0.046
Sift	Benign	0.17	T
Sift4G	Benign	0.56	T
Polyphen		0.24	B
Vest4		0.12
MutPred		0.38		Loss of ubiquitination at K752 (P = 0.0071);
MVP		0.57
MPC		0.41
ClinPred		0.092	T
GERP RS		5.7
Varity_R		0.26
gMVP		0.35

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1452944576; hg19: chrX-99658555;