rs184545774

chrX-100296444-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001184880.2(PCDH19):c.3280C>G(p.Leu1094Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00247 in 1,209,488 control chromosomes in the GnomAD database, including 2 homozygotes. There are 951 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0015 (0 hom., 46 hem., cov: 22)
  • Exomes 𝑓: 0.0026 (2 hom. 905 hem.)
• Consequence: PCDH19 NM_001184880.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 1.83

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0055009425).
• BP6: Variant X-100296444-G-C is Benign according to our data. Variant chrX-100296444-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 138593.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-100296444-G-C is described in Lovd as [Likely_benign]. Variant chrX-100296444-G-C is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0015 (167/111375) while in subpopulation NFE AF= 0.00232 (123/53088). AF 95% confidence interval is 0.00198. There are 0 homozygotes in gnomad4. There are 46 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd at 46 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCDH19	NM_001184880.2	c.3280C>G	p.Leu1094Val	missense_variant	6/6	ENST00000373034.8
PCDH19	NM_001105243.2	c.3139C>G	p.Leu1047Val	missense_variant	5/5
PCDH19	NM_020766.3	c.3136C>G	p.Leu1046Val	missense_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCDH19	ENST00000373034.8	c.3280C>G	p.Leu1094Val	missense_variant	6/6	1	NM_001184880.2	A1
PCDH19	ENST00000255531.8	c.3139C>G	p.Leu1047Val	missense_variant	5/5	1		P5
PCDH19	ENST00000420881.6	c.3136C>G	p.Leu1046Val	missense_variant	5/5	1		A1

Frequencies

GnomAD3 genomes AF: 0.00150 AC: 167 AN: 111318 Hom.: 0 Cov.: 22 AF XY: 0.00137 AC XY: 46 AN XY: 33498

Gnomad AFR AF: 0.000262

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00219

Gnomad ASJ AF: 0.00304

Gnomad EAS AF: 0.000564

Gnomad SAS AF: 0.000391

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00418

Gnomad NFE AF: 0.00232

Gnomad OTH AF: 0.000669

GnomAD3 exomes AF: 0.00148 AC: 269 AN: 181515 Hom.: 0 AF XY: 0.00150 AC XY: 101 AN XY: 67467

Gnomad AFR exome AF: 0.000161

Gnomad AMR exome AF: 0.000402

Gnomad ASJ exome AF: 0.00214

Gnomad EAS exome AF: 0.000443

Gnomad SAS exome AF: 0.00110

Gnomad FIN exome AF: 0.000189

Gnomad NFE exome AF: 0.00246

Gnomad OTH exome AF: 0.00224

GnomAD4 exome AF: 0.00256 AC: 2815 AN: 1098113 Hom.: 2 Cov.: 30 AF XY: 0.00249 AC XY: 905 AN XY: 363469

Gnomad4 AFR exome AF: 0.000227

Gnomad4 AMR exome AF: 0.000540

Gnomad4 ASJ exome AF: 0.00201

Gnomad4 EAS exome AF: 0.00103

Gnomad4 SAS exome AF: 0.000997

Gnomad4 FIN exome AF: 0.0000987

Gnomad4 NFE exome AF: 0.00302

Gnomad4 OTH exome AF: 0.00230

GnomAD4 genome AF: 0.00150 AC: 167 AN: 111375 Hom.: 0 Cov.: 22 AF XY: 0.00137 AC XY: 46 AN XY: 33565

Gnomad4 AFR AF: 0.000261

Gnomad4 AMR AF: 0.00218

Gnomad4 ASJ AF: 0.00304

Gnomad4 EAS AF: 0.000566

Gnomad4 SAS AF: 0.000392

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00232

Gnomad4 OTH AF: 0.000660

Alfa AF: 0.00223 Hom.: 46

Bravo AF: 0.00171

TwinsUK AF: 0.00270 AC: 10

ALSPAC AF: 0.00346 AC: 10

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00351 AC: 23

ExAC AF: 0.00150 AC: 181

EpiCase AF: 0.00202

EpiControl AF: 0.00279

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Mar 03, 2017	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 14, 2013	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 23, 2015	- -

Developmental and epileptic encephalopathy, 9 Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Human Genetics, Inc, Center for Human Genetics, Inc	Nov 01, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 09, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 22, 2018

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.77
Cadd	Benign	12
Dann	Benign	0.25
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.67	T;T;T
M_CAP	Uncertain	0.24	D
MetaRNN	Benign	0.0055	T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.94	N;N;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	0.010	N;N;N
REVEL	Benign	0.086
Sift	Benign	0.67	T;T;T
Sift4G	Benign	0.92	T;T;T
Polyphen		0.0	.;B;B
Vest4		0.094
MVP		0.37
MPC		0.51
ClinPred		0.0036	T
GERP RS		1.4
Varity_R		0.079
gMVP		0.21

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: rs184545774; hg19: chrX-99551442;