rs200471732

chrX-100406873-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001184880.2(PCDH19):c.1725C>T(p.Val575=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000244 in 1,210,158 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 105 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00027 (0 hom., 9 hem., cov: 24)
  • Exomes 𝑓: 0.00024 (0 hom. 96 hem.)
• Consequence: PCDH19 NM_001184880.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 1.22

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant X-100406873-G-A is Benign according to our data. Variant chrX-100406873-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 138600.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-100406873-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=1.22 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000268 (30/111992) while in subpopulation AMR AF= 0.00103 (11/10650). AF 95% confidence interval is 0.000579. There are 0 homozygotes in gnomad4. There are 9 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd at 8 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCDH19	NM_001184880.2	c.1725C>T	p.Val575=	synonymous_variant	1/6	ENST00000373034.8
PCDH19	NM_001105243.2	c.1725C>T	p.Val575=	synonymous_variant	1/5
PCDH19	NM_020766.3	c.1725C>T	p.Val575=	synonymous_variant	1/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCDH19	ENST00000373034.8	c.1725C>T	p.Val575=	synonymous_variant	1/6	1	NM_001184880.2	A1
PCDH19	ENST00000255531.8	c.1725C>T	p.Val575=	synonymous_variant	1/5	1		P5
PCDH19	ENST00000420881.6	c.1725C>T	p.Val575=	synonymous_variant	1/5	1		A1

Frequencies

GnomAD3 genomes AF: 0.000259 AC: 29 AN: 111939 Hom.: 0 Cov.: 24 AF XY: 0.000235 AC XY: 8 AN XY: 34095

Gnomad AFR AF: 0.0000650

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00103

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000379

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00420

Gnomad NFE AF: 0.000226

Gnomad OTH AF: 0.00133

GnomAD3 exomes AF: 0.000518 AC: 94 AN: 181584 Hom.: 0 AF XY: 0.000474 AC XY: 32 AN XY: 67440

Gnomad AFR exome AF: 0.0000806

Gnomad AMR exome AF: 0.00212

Gnomad ASJ exome AF: 0.000134

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000210

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000283

Gnomad OTH exome AF: 0.00157

GnomAD4 exome AF: 0.000241 AC: 265 AN: 1098166 Hom.: 0 Cov.: 32 AF XY: 0.000264 AC XY: 96 AN XY: 363524

Gnomad4 AFR exome AF: 0.000189

Gnomad4 AMR exome AF: 0.00199

Gnomad4 ASJ exome AF: 0.000155

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000185

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000165

Gnomad4 OTH exome AF: 0.000325

GnomAD4 genome AF: 0.000268 AC: 30 AN: 111992 Hom.: 0 Cov.: 24 AF XY: 0.000263 AC XY: 9 AN XY: 34158

Gnomad4 AFR AF: 0.0000648

Gnomad4 AMR AF: 0.00103

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000760

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000226

Gnomad4 OTH AF: 0.00132

Alfa AF: 0.000608 Hom.: 4

Bravo AF: 0.000332

EpiCase AF: 0.000545

EpiControl AF: 0.000711

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	PCDH19: BP4, BP7, BS2 -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 15, 2018	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 21, 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	Dec 31, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 07, 2016	- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 20, 2017

This alteration is classified as likely 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

Jan 27, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
Cadd	Benign	5.8
Dann	Benign	0.58

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: rs200471732; hg19: chrX-99661871;