rs111960928

Positions:

• chrX-100402718-T-A
• chrX-100402718-T-C
• chrX-100402718-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.2422A>T​(p.Thr808Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000912 in 1,096,704 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: PCDH19 NM_001184880.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.96

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=0.23477602).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCDH19	NM_001184880.2	c.2422A>T	p.Thr808Ser	missense_variant	3/6	ENST00000373034.8	NP_001171809.1
PCDH19	NM_001105243.2	c.2281A>T	p.Thr761Ser	missense_variant	2/5		NP_001098713.1
PCDH19	NM_020766.3	c.2281A>T	p.Thr761Ser	missense_variant	2/5		NP_065817.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCDH19	ENST00000373034.8	c.2422A>T	p.Thr808Ser	missense_variant	3/6	1	NM_001184880.2	ENSP00000362125.4
PCDH19	ENST00000255531.8	c.2281A>T	p.Thr761Ser	missense_variant	2/5	1		ENSP00000255531.7
PCDH19	ENST00000420881.6	c.2281A>T	p.Thr761Ser	missense_variant	2/5	1		ENSP00000400327.2
PCDH19	ENST00000636150.1	c.66-143A>T		intron_variant		5		ENSP00000490463.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD3 exomes AF: 0.00000551 AC: 1 AN: 181556 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 67398

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000366

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: 9.12e-7 AC: 1 AN: 1096704 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 362094

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000284

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

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

Labcorp Genetics (formerly Invitae), Labcorp

Aug 22, 2022

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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 408907). This variant has not been reported in the literature in individuals affected with PCDH19-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.004%). This sequence change replaces threonine, which is neutral and polar, with serine, which is neutral and polar, at codon 808 of the PCDH19 protein (p.Thr808Ser). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.49
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.41
CADD	Uncertain	25
DANN	Benign	0.90
DEOGEN2	Benign	0.020	.;T;.
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.85	D;D;D
M_CAP	Uncertain	0.24	D
MetaRNN	Benign	0.23	T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.34	.;N;.
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	0.24	N;N;N
REVEL	Benign	0.12
Sift	Benign	0.73	T;T;T
Sift4G	Benign	0.84	T;T;T
Polyphen		1.0, 0.38	.;D;B
Vest4		0.36
MutPred		0.40		.;Gain of relative solvent accessibility (P = 0.0023);.;
MVP		0.79
MPC		0.82
ClinPred		0.35	T
GERP RS		5.6
Varity_R		0.25
gMVP		0.34

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: rs111960928; hg19: chrX-99657716;