rs56307810

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001184880.2(PCDH19):c.81C>T(p.Tyr27Tyr) 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

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 4.41

Variant links:

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]

PCDH19 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 GnomAd4 at 7 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCDH19	NM_001184880.2 link	c.81C>T	p.Tyr27Tyr	synonymous_variant	1/6	ENST00000373034.8	NP_001171809.1	Q8TAB3-1
PCDH19	NM_001105243.2 link	c.81C>T	p.Tyr27Tyr	synonymous_variant	1/5		NP_001098713.1	Q8TAB3-2B3KU71
PCDH19	NM_020766.3 link	c.81C>T	p.Tyr27Tyr	synonymous_variant	1/5		NP_065817.2	Q8TAB3-3B3KU71

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
PCDH19	ENST00000373034.8 link	c.81C>T	p.Tyr27Tyr	synonymous_variant	1/6	1	NM_001184880.2	ENSP00000362125.4	Q8TAB3-1
PCDH19	ENST00000255531.8 link	c.81C>T	p.Tyr27Tyr	synonymous_variant	1/5	1		ENSP00000255531.7	Q8TAB3-2
PCDH19	ENST00000420881.6 link	c.81C>T	p.Tyr27Tyr	synonymous_variant	1/5	1		ENSP00000400327.2	Q8TAB3-3

Frequencies

GnomAD3 genomes

AF:

0.00912

AC:

1018

AN:

111630

Hom.:

Cov.:

AF XY:

0.00801

AC XY:

271

AN XY:

33820

show subpopulations

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.:

AF XY:

0.00671

AC XY:

348

AN XY:

51826

show subpopulations

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.:

Cov.:

AF XY:

0.0119

AC XY:

4266

AN XY:

357101

show subpopulations

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.:

Cov.:

AF XY:

0.00800

AC XY:

271

AN XY:

33874

show subpopulations

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.:

Bravo

AF:

0.00703

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

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	- -

not provided

Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Developmental and epileptic encephalopathy, 9

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Aug 31, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

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. -

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over