X-100296318-CTT-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PVS1_Moderate BS2

The NM_001184880.2(PCDH19):c.3404_3405del(p.Lys1135ArgfsTer28) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000268 in 111,942 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. K1135K) has been classified as Likely benign.

• Frequency: Genomes: 𝑓 0.000027 (0 hom., 2 hem., cov: 22)
• Consequence: PCDH19 NM_001184880.2 frameshift
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 4.65

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 Likely_benign. Variant got -2 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0125 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• BS2: High Hemizygotes in GnomAd at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCDH19	NM_001184880.2	c.3404_3405del	p.Lys1135ArgfsTer28	frameshift_variant	6/6	ENST00000373034.8
PCDH19	NM_001105243.2	c.3263_3264del	p.Lys1088ArgfsTer28	frameshift_variant	5/5
PCDH19	NM_020766.3	c.3260_3261del	p.Lys1087ArgfsTer28	frameshift_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCDH19	ENST00000373034.8	c.3404_3405del	p.Lys1135ArgfsTer28	frameshift_variant	6/6	1	NM_001184880.2	A1
PCDH19	ENST00000255531.8	c.3263_3264del	p.Lys1088ArgfsTer28	frameshift_variant	5/5	1		P5
PCDH19	ENST00000420881.6	c.3260_3261del	p.Lys1087ArgfsTer28	frameshift_variant	5/5	1		A1
PCDH19	ENST00000464981.1			upstream_gene_variant		3

Frequencies

GnomAD3 genomes AF: 0.0000268 AC: 3 AN: 111942 Hom.: 0 Cov.: 22 AF XY: 0.0000586 AC XY: 2 AN XY: 34110

Gnomad AFR AF: 0.0000975

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0000268 AC: 3 AN: 111942 Hom.: 0 Cov.: 22 AF XY: 0.0000586 AC XY: 2 AN XY: 34110

Gnomad4 AFR AF: 0.0000975

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Developmental and epileptic encephalopathy, 9 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Aug 29, 2022	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. ClinVar contains an entry for this variant (Variation ID: 804048). This variant is also known as c.3263_3264delAA (p.Lys1088ArgfsX28). This frameshift has been observed in individual(s) with developmental and epileptic encephalopathy (PMID: 31054490). This variant is present in population databases (no rsID available, gnomAD 0.02%). This sequence change results in a frameshift in the PCDH19 gene (p.Lys1135Argfs*28). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 14 amino acid(s) of the PCDH19 protein and extend the protein by 13 additional amino acid residues. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Oct 04, 2023

Identified de novo hemizygous in a male with developmental delay, microcephaly, and intractable seizures, however pathogenic variants in the PCDH19 gene are inherited in an unusual X-linked manner and hemizygous male carriers are typically unaffected (Nashabat et al., 2019); Frameshift variant predicted to result in protein extension as the last 14 amino acids are lost and replaced with 27 incorrect amino acids, loss-of-function variants have not been reported downstream of this position in the protein; This variant is associated with the following publications: (PMID: 31054490) -

Computational scores

Source: dbNSFP v4.3

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: rs999749949; hg19: chrX-99551316;