rs193148631

Positions:

• chrX-100341955-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_001184880.2(PCDH19):​c.2796C>T​(p.Asn932Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00326 in 1,207,622 control chromosomes in the GnomAD database, including 6 homozygotes. There are 1,317 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0024 (1 hom., 76 hem., cov: 23)
  • Exomes 𝑓: 0.0034 (5 hom. 1241 hem.)
• Consequence: PCDH19 NM_001184880.2 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:7
• Conservation: PhyloP100: -0.133

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant X-100341955-G-A is Benign according to our data. Variant chrX-100341955-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 138601.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2, Benign=3}. Variant chrX-100341955-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.133 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00237 (265/111965) while in subpopulation SAS AF= 0.00453 (12/2647). AF 95% confidence interval is 0.00319. There are 1 homozygotes in gnomad4. There are 76 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd4 at 76 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCDH19	NM_001184880.2	c.2796C>T	p.Asn932Asn	synonymous_variant	5/6	ENST00000373034.8	NP_001171809.1
PCDH19	NM_001105243.2	c.2655C>T	p.Asn885Asn	synonymous_variant	4/5		NP_001098713.1
PCDH19	NM_020766.3	c.2652C>T	p.Asn884Asn	synonymous_variant	4/5		NP_065817.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCDH19	ENST00000373034.8	c.2796C>T	p.Asn932Asn	synonymous_variant	5/6	1	NM_001184880.2	ENSP00000362125.4
PCDH19	ENST00000255531.8	c.2655C>T	p.Asn885Asn	synonymous_variant	4/5	1		ENSP00000255531.7
PCDH19	ENST00000420881.6	c.2652C>T	p.Asn884Asn	synonymous_variant	4/5	1		ENSP00000400327.2

Frequencies

GnomAD3 genomes AF: 0.00236 AC: 264 AN: 111915 Hom.: 1 Cov.: 23 AF XY: 0.00220 AC XY: 75 AN XY: 34099

Gnomad AFR AF: 0.000974

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00133

Gnomad ASJ AF: 0.00415

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00414

Gnomad FIN AF: 0.000328

Gnomad MID AF: 0.00417

Gnomad NFE AF: 0.00361

Gnomad OTH AF: 0.00199

GnomAD3 exomes AF: 0.00274 AC: 498 AN: 181689 Hom.: 0 AF XY: 0.00289 AC XY: 195 AN XY: 67533

Gnomad AFR exome AF: 0.00105

Gnomad AMR exome AF: 0.00252

Gnomad ASJ exome AF: 0.00388

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00394

Gnomad FIN exome AF: 0.0000628

Gnomad NFE exome AF: 0.00354

Gnomad OTH exome AF: 0.00516

GnomAD4 exome AF: 0.00335 AC: 3672 AN: 1095657 Hom.: 5 Cov.: 31 AF XY: 0.00344 AC XY: 1241 AN XY: 361097

Gnomad4 AFR exome AF: 0.000873

Gnomad4 AMR exome AF: 0.00236

Gnomad4 ASJ exome AF: 0.00346

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00361

Gnomad4 FIN exome AF: 0.000148

Gnomad4 NFE exome AF: 0.00370

Gnomad4 OTH exome AF: 0.00352

GnomAD4 genome AF: 0.00237 AC: 265 AN: 111965 Hom.: 1 Cov.: 23 AF XY: 0.00222 AC XY: 76 AN XY: 34159

Gnomad4 AFR AF: 0.000972

Gnomad4 AMR AF: 0.00133

Gnomad4 ASJ AF: 0.00415

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00453

Gnomad4 FIN AF: 0.000328

Gnomad4 NFE AF: 0.00361

Gnomad4 OTH AF: 0.00131

Alfa AF: 0.00373 Hom.: 27

Bravo AF: 0.00241

EpiCase AF: 0.00540

EpiControl AF: 0.00587

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Oct 31, 2014	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 19, 2012	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)	Nov 18, 2014	- -

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Developmental and epileptic encephalopathy, 9 Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 15, 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, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 05, 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	-0.73
CADD	Benign	0.46
DANN	Benign	0.68

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: rs193148631; hg19: chrX-99596953;