rs368963363

Positions:

• chrX-100407710-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.888C>T​(p.Gly296=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00023 in 1,211,236 control chromosomes in the GnomAD database, including 1 homozygotes. There are 150 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., 10 hem., cov: 25)
  • Exomes 𝑓: 0.00024 (1 hom. 140 hem.)
• Consequence: PCDH19 NM_001184880.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.466

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=-0.64).
• BP6: Variant X-100407710-G-A is Benign according to our data. Variant chrX-100407710-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 138598.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.466 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000168 (19/113013) while in subpopulation SAS AF= 0.00473 (13/2748). AF 95% confidence interval is 0.0028. There are 0 homozygotes in gnomad4. There are 10 alleles in male gnomad4 subpopulation. Median coverage is 25. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd4 at 10 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCDH19	NM_001184880.2	c.888C>T	p.Gly296=	synonymous_variant	1/6	ENST00000373034.8
PCDH19	NM_001105243.2	c.888C>T	p.Gly296=	synonymous_variant	1/5
PCDH19	NM_020766.3	c.888C>T	p.Gly296=	synonymous_variant	1/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCDH19	ENST00000373034.8	c.888C>T	p.Gly296=	synonymous_variant	1/6	1	NM_001184880.2	A1
PCDH19	ENST00000255531.8	c.888C>T	p.Gly296=	synonymous_variant	1/5	1		P5
PCDH19	ENST00000420881.6	c.888C>T	p.Gly296=	synonymous_variant	1/5	1		A1

Frequencies

GnomAD3 genomes AF: 0.000168 AC: 19 AN: 112962 Hom.: 0 Cov.: 25 AF XY: 0.000285 AC XY: 10 AN XY: 35102

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000281

Gnomad SAS AF: 0.00472

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000563

Gnomad OTH AF: 0.00131

GnomAD3 exomes AF: 0.000529 AC: 96 AN: 181633 Hom.: 0 AF XY: 0.000726 AC XY: 49 AN XY: 67501

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000365

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00425

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000135

Gnomad OTH exome AF: 0.000672

GnomAD4 exome AF: 0.000236 AC: 259 AN: 1098223 Hom.: 1 Cov.: 33 AF XY: 0.000385 AC XY: 140 AN XY: 363581

Gnomad4 AFR exome AF: 0.0000379

Gnomad4 AMR exome AF: 0.0000284

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000331

Gnomad4 SAS exome AF: 0.00336

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000594

Gnomad4 OTH exome AF: 0.000521

GnomAD4 genome AF: 0.000168 AC: 19 AN: 113013 Hom.: 0 Cov.: 25 AF XY: 0.000284 AC XY: 10 AN XY: 35163

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000281

Gnomad4 SAS AF: 0.00473

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000563

Gnomad4 OTH AF: 0.00129

Alfa AF: 0.000218 Hom.: 2

Bravo AF: 0.0000529

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Apr 17, 2014

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. -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 14, 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

Dec 11, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	10
DANN	Benign	0.76

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: rs368963363; hg19: chrX-99662708;