rs56307810

chrX-100408517-G-AchrX-100408517-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001184880.2(PCDH19):c.81C>T(p.Tyr27=) variant causes a synonymous change. The variant allele was found at a frequency of 0.0123 in 1,199,655 control chromosomes in the GnomAD database, including 89 homozygotes. There are 4,537 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 0.0091 (7 hom., 271 hem., cov: 23)
  • Exomes 𝑓: 0.013 (82 hom. 4266 hem.)
• Consequence: PCDH19 NM_001184880.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 4.41

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant X-100408517-G-A is Benign according to our data. Variant chrX-100408517-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 93680.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-100408517-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00912 (1018/111674) while in subpopulation NFE AF= 0.0153 (812/52957). AF 95% confidence interval is 0.0145. There are 7 homozygotes in gnomad4. There are 271 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 7 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCDH19	NM_001184880.2	c.81C>T	p.Tyr27=	synonymous_variant	1/6	ENST00000373034.8
PCDH19	NM_001105243.2	c.81C>T	p.Tyr27=	synonymous_variant	1/5
PCDH19	NM_020766.3	c.81C>T	p.Tyr27=	synonymous_variant	1/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCDH19	ENST00000373034.8	c.81C>T	p.Tyr27=	synonymous_variant	1/6	1	NM_001184880.2	A1
PCDH19	ENST00000255531.8	c.81C>T	p.Tyr27=	synonymous_variant	1/5	1		P5
PCDH19	ENST00000420881.6	c.81C>T	p.Tyr27=	synonymous_variant	1/5	1		A1

Frequencies

GnomAD3 genomes AF: 0.00912 AC: 1018 AN: 111630 Hom.: 7 Cov.: 23 AF XY: 0.00801 AC XY: 271 AN XY: 33820

Gnomad AFR AF: 0.00218

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00159

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00267

Gnomad FIN AF: 0.0178

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0153

Gnomad OTH AF: 0.00536

GnomAD3 exomes AF: 0.00825 AC: 1296 AN: 157008 Hom.: 11 AF XY: 0.00671 AC XY: 348 AN XY: 51826

Gnomad AFR exome AF: 0.00174

Gnomad AMR exome AF: 0.000990

Gnomad ASJ exome AF: 0.000429

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00219

Gnomad FIN exome AF: 0.0223

Gnomad NFE exome AF: 0.0138

Gnomad OTH exome AF: 0.00675

GnomAD4 exome AF: 0.0126 AC: 13686 AN: 1087981 Hom.: 82 Cov.: 32 AF XY: 0.0119 AC XY: 4266 AN XY: 357101

Gnomad4 AFR exome AF: 0.00171

Gnomad4 AMR exome AF: 0.00158

Gnomad4 ASJ exome AF: 0.000519

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00238

Gnomad4 FIN exome AF: 0.0229

Gnomad4 NFE exome AF: 0.0145

Gnomad4 OTH exome AF: 0.00947

GnomAD4 genome AF: 0.00912 AC: 1018 AN: 111674 Hom.: 7 Cov.: 23 AF XY: 0.00800 AC XY: 271 AN XY: 33874

Gnomad4 AFR AF: 0.00217

Gnomad4 AMR AF: 0.00159

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00268

Gnomad4 FIN AF: 0.0178

Gnomad4 NFE AF: 0.0153

Gnomad4 OTH AF: 0.00529

Alfa AF: 0.0117 Hom.: 91

Bravo AF: 0.00703

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jul 29, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 21, 2013	- -

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	Aug 31, 2021	- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 25, 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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
Cadd	Benign	7.1
Dann	Benign	0.73

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: rs56307810; hg19: chrX-99663515;