rs3764758

chrX-100296786-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001184880.2(PCDH19):c.2938C>T(p.Arg980Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00131 in 1,209,314 control chromosomes in the GnomAD database, including 21 homozygotes. There are 488 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R980H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0020 (3 hom., 79 hem., cov: 22)
  • Exomes 𝑓: 0.0012 (18 hom. 409 hem.)
• Consequence: PCDH19 NM_001184880.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 4.52

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=0.010465592).
• BP6: Variant X-100296786-G-A is Benign according to our data. Variant chrX-100296786-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 138590.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-100296786-G-A is described in Lovd as [Likely_benign]. Variant chrX-100296786-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0501 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCDH19	NM_001184880.2	c.2938C>T	p.Arg980Cys	missense_variant	6/6	ENST00000373034.8
PCDH19	NM_001105243.2	c.2797C>T	p.Arg933Cys	missense_variant	5/5
PCDH19	NM_020766.3	c.2794C>T	p.Arg932Cys	missense_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCDH19	ENST00000373034.8	c.2938C>T	p.Arg980Cys	missense_variant	6/6	1	NM_001184880.2	A1
PCDH19	ENST00000255531.8	c.2797C>T	p.Arg933Cys	missense_variant	5/5	1		P5
PCDH19	ENST00000420881.6	c.2794C>T	p.Arg932Cys	missense_variant	5/5	1		A1

Frequencies

GnomAD3 genomes AF: 0.00204 AC: 228 AN: 111790 Hom.: 3 Cov.: 22 AF XY: 0.00233 AC XY: 79 AN XY: 33946

Gnomad AFR AF: 0.000488

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000189

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0563

Gnomad SAS AF: 0.00270

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000752

Gnomad OTH AF: 0.000665

GnomAD3 exomes AF: 0.00479 AC: 870 AN: 181478 Hom.: 22 AF XY: 0.00405 AC XY: 273 AN XY: 67446

Gnomad AFR exome AF: 0.000645

Gnomad AMR exome AF: 0.000110

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0609

Gnomad SAS exome AF: 0.00136

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000246

Gnomad OTH exome AF: 0.00135

GnomAD4 exome AF: 0.00124 AC: 1359 AN: 1097470 Hom.: 18 Cov.: 30 AF XY: 0.00113 AC XY: 409 AN XY: 362840

Gnomad4 AFR exome AF: 0.000303

Gnomad4 AMR exome AF: 0.000114

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0377

Gnomad4 SAS exome AF: 0.00139

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000357

Gnomad4 OTH exome AF: 0.00224

GnomAD4 genome AF: 0.00204 AC: 228 AN: 111844 Hom.: 3 Cov.: 22 AF XY: 0.00232 AC XY: 79 AN XY: 34010

Gnomad4 AFR AF: 0.000487

Gnomad4 AMR AF: 0.000188

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0565

Gnomad4 SAS AF: 0.00270

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000752

Gnomad4 OTH AF: 0.000657

Alfa AF: 0.00200 Hom.: 28

Bravo AF: 0.00244

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000346 AC: 1

ESP6500AA AF: 0.000838 AC: 3

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00452 AC: 547

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 27, 2014	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 17, 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. -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Mar 27, 2013	- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 18, 2016

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. -

Developmental and epileptic encephalopathy, 9 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.32
Cadd	Benign	20
Dann	Uncertain	1.0
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.90	D;D;D
MetaRNN	Benign	0.010	T;T;T
MetaSVM	Benign	-0.66	T
MutationTaster	Benign	1.2e-9	P;P;P
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-2.0	N;N;N
REVEL	Benign	0.15
Sift	Benign	0.064	T;T;T
Sift4G	Uncertain	0.046	D;D;D
Polyphen		0.0020, 1.0	.;B;D
Vest4		0.15
MVP		0.67
MPC		0.69
ClinPred		0.016	T
GERP RS		4.1
Varity_R		0.14
gMVP		0.52

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: rs3764758; hg19: chrX-99551784;