rs754570811

Positions:

• chrX-100342057-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_001184880.2(PCDH19):​c.2694C>T​(p.Asp898=) variant causes a synonymous change. The variant allele was found at a frequency of 0.00000456 in 1,095,578 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 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: not found (cov: 23)
  • Exomes 𝑓: 0.0000046 (0 hom. 3 hem.)
• Consequence: PCDH19 NM_001184880.2 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 3.96

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant X-100342057-G-A is Benign according to our data. Variant chrX-100342057-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 211838.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
• BS2: High Hemizygotes in GnomAdExome4 at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCDH19	NM_001184880.2	c.2694C>T	p.Asp898=	synonymous_variant	5/6	ENST00000373034.8	NP_001171809.1
PCDH19	NM_001105243.2	c.2553C>T	p.Asp851=	synonymous_variant	4/5		NP_001098713.1
PCDH19	NM_020766.3	c.2550C>T	p.Asp850=	synonymous_variant	4/5		NP_065817.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCDH19	ENST00000373034.8	c.2694C>T	p.Asp898=	synonymous_variant	5/6	1	NM_001184880.2	ENSP00000362125	A1
PCDH19	ENST00000255531.8	c.2553C>T	p.Asp851=	synonymous_variant	4/5	1		ENSP00000255531	P5
PCDH19	ENST00000420881.6	c.2550C>T	p.Asp850=	synonymous_variant	4/5	1		ENSP00000400327	A1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000456 AC: 5 AN: 1095578 Hom.: 0 Cov.: 31 AF XY: 0.00000831 AC XY: 3 AN XY: 360954

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000476

Gnomad4 OTH exome AF: 0.0000217

GnomAD4 genome Cov.: 23

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Apr 22, 2015

- -

Developmental and epileptic encephalopathy, 9 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 26, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	5.6
DANN	Benign	0.56

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs754570811; hg19: chrX-99597055;