rs377627937

chrX-100407943-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.655C>T(p.Leu219=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000123 in 1,209,602 control chromosomes in the GnomAD database, including 1 homozygotes. There are 40 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 0.00017 (0 hom., 2 hem., cov: 24)
  • Exomes 𝑓: 0.00012 (1 hom. 38 hem.)
• Consequence: PCDH19 NM_001184880.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.0250

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=-0.89).
• BP6: Variant X-100407943-G-A is Benign according to our data. Variant chrX-100407943-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 93678.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-100407943-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.025 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000168 (19/113430) while in subpopulation EAS AF= 0.00112 (4/3574). AF 95% confidence interval is 0.000498. There are 0 homozygotes in gnomad4. There are 2 alleles in male gnomad4 subpopulation. Median coverage is 24. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCDH19	NM_001184880.2	c.655C>T	p.Leu219=	synonymous_variant	1/6	ENST00000373034.8
PCDH19	NM_001105243.2	c.655C>T	p.Leu219=	synonymous_variant	1/5
PCDH19	NM_020766.3	c.655C>T	p.Leu219=	synonymous_variant	1/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCDH19	ENST00000373034.8	c.655C>T	p.Leu219=	synonymous_variant	1/6	1	NM_001184880.2	A1
PCDH19	ENST00000255531.8	c.655C>T	p.Leu219=	synonymous_variant	1/5	1		P5
PCDH19	ENST00000420881.6	c.655C>T	p.Leu219=	synonymous_variant	1/5	1		A1

Frequencies

GnomAD3 genomes AF: 0.000168 AC: 19 AN: 113430 Hom.: 0 Cov.: 24 AF XY: 0.0000562 AC XY: 2 AN XY: 35562

Gnomad AFR AF: 0.0000959

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000919

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00112

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00130

GnomAD3 exomes AF: 0.000100 AC: 18 AN: 179580 Hom.: 0 AF XY: 0.0000757 AC XY: 5 AN XY: 66030

Gnomad AFR exome AF: 0.000161

Gnomad AMR exome AF: 0.0000365

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000590

Gnomad SAS exome AF: 0.000105

Gnomad FIN exome AF: 0.0000715

Gnomad NFE exome AF: 0.0000246

Gnomad OTH exome AF: 0.000450

GnomAD4 exome AF: 0.000119 AC: 130 AN: 1096172 Hom.: 1 Cov.: 33 AF XY: 0.000105 AC XY: 38 AN XY: 362158

Gnomad4 AFR exome AF: 0.0000758

Gnomad4 AMR exome AF: 0.0000852

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000530

Gnomad4 SAS exome AF: 0.0000185

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000226

Gnomad4 OTH exome AF: 0.00193

GnomAD4 genome AF: 0.000168 AC: 19 AN: 113430 Hom.: 0 Cov.: 24 AF XY: 0.0000562 AC XY: 2 AN XY: 35562

Gnomad4 AFR AF: 0.0000959

Gnomad4 AMR AF: 0.000919

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00112

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00130

Alfa AF: 0.000285 Hom.: 1

Bravo AF: 0.000193

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 02, 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	Eurofins Ntd Llc (ga)	Jan 12, 2016	- -

Developmental and epileptic encephalopathy, 9 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 24, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Mar 21, 2022	- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 24, 2016

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. -

PCDH19-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 11, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
Cadd	Benign	0.81
Dann	Benign	0.65

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: rs377627937; hg19: chrX-99662941;