rs56277715

chrX-100407461-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.1137C>T(p.Gly379=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0153 in 1,210,690 control chromosomes in the GnomAD database, including 117 homozygotes. There are 5,816 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 0.010 (5 hom., 342 hem., cov: 24)
  • Exomes 𝑓: 0.016 (112 hom. 5474 hem.)
• Consequence: PCDH19 NM_001184880.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.0170

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-100407461-G-A is Benign according to our data. Variant chrX-100407461-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 93670.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-100407461-G-A is described in Lovd as [Likely_benign]. Variant chrX-100407461-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.017 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0104 (1175/112900) while in subpopulation NFE AF= 0.0173 (922/53309). AF 95% confidence interval is 0.0164. There are 5 homozygotes in gnomad4. There are 342 alleles in male gnomad4 subpopulation. Median coverage is 24. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 5 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCDH19	NM_001184880.2	c.1137C>T	p.Gly379=	synonymous_variant	1/6	ENST00000373034.8
PCDH19	NM_001105243.2	c.1137C>T	p.Gly379=	synonymous_variant	1/5
PCDH19	NM_020766.3	c.1137C>T	p.Gly379=	synonymous_variant	1/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCDH19	ENST00000373034.8	c.1137C>T	p.Gly379=	synonymous_variant	1/6	1	NM_001184880.2	A1
PCDH19	ENST00000255531.8	c.1137C>T	p.Gly379=	synonymous_variant	1/5	1		P5
PCDH19	ENST00000420881.6	c.1137C>T	p.Gly379=	synonymous_variant	1/5	1		A1

Frequencies

GnomAD3 genomes AF: 0.0104 AC: 1176 AN: 112846 Hom.: 5 Cov.: 24 AF XY: 0.00980 AC XY: 343 AN XY: 35012

Gnomad AFR AF: 0.00219

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0102

Gnomad ASJ AF: 0.00151

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00820

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0173

Gnomad OTH AF: 0.0132

GnomAD3 exomes AF: 0.0102 AC: 1847 AN: 180854 Hom.: 17 AF XY: 0.0102 AC XY: 681 AN XY: 66760

Gnomad AFR exome AF: 0.00161

Gnomad AMR exome AF: 0.00764

Gnomad ASJ exome AF: 0.00362

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00833

Gnomad NFE exome AF: 0.0174

Gnomad OTH exome AF: 0.0117

GnomAD4 exome AF: 0.0158 AC: 17331 AN: 1097790 Hom.: 112 Cov.: 33 AF XY: 0.0151 AC XY: 5474 AN XY: 363222

Gnomad4 AFR exome AF: 0.00250

Gnomad4 AMR exome AF: 0.00829

Gnomad4 ASJ exome AF: 0.00356

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000369

Gnomad4 FIN exome AF: 0.00870

Gnomad4 NFE exome AF: 0.0189

Gnomad4 OTH exome AF: 0.0134

GnomAD4 genome AF: 0.0104 AC: 1175 AN: 112900 Hom.: 5 Cov.: 24 AF XY: 0.00975 AC XY: 342 AN XY: 35076

Gnomad4 AFR AF: 0.00218

Gnomad4 AMR AF: 0.0102

Gnomad4 ASJ AF: 0.00151

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00820

Gnomad4 NFE AF: 0.0173

Gnomad4 OTH AF: 0.0131

Alfa AF: 0.0121 Hom.: 101

Bravo AF: 0.0109

EpiCase AF: 0.0153

EpiControl AF: 0.0164

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 26, 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	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 16, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Developmental and epileptic encephalopathy, 9 Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 20, 2021	- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 08, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
Cadd	Benign	7.4
Dann	Benign	0.71

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: rs56277715; hg19: chrX-99662459;