rs863224907

Variant names:

• chrX-100408140-GC-AT
• rs863224907
• NM_001184880.2:c.457_458delGCinsAT

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PM5 PP3 PP5

The NM_001184880.2(PCDH19):​c.457_458delGCinsAT​(p.Ala153Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A153T) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 24)
• Consequence: PCDH19 NM_001184880.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 9.94

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_pathogenic. Variant got 8 ACMG points.

• PM1: In a domain Cadherin 2 (size 108) in uniprot entity PCD19_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_001184880.2
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant X-100408140-GC-AT is Pathogenic according to our data. Variant chrX-100408140-GC-AT is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 216981.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCDH19	NM_001184880.2	c.457_458delGCinsAT	p.Ala153Ile	missense_variant		ENST00000373034.8	NP_001171809.1
PCDH19	NM_001105243.2	c.457_458delGCinsAT	p.Ala153Ile	missense_variant			NP_001098713.1
PCDH19	NM_020766.3	c.457_458delGCinsAT	p.Ala153Ile	missense_variant			NP_065817.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCDH19	ENST00000373034.8	c.457_458delGCinsAT	p.Ala153Ile	missense_variant		1	NM_001184880.2	ENSP00000362125.4
PCDH19	ENST00000255531.8	c.457_458delGCinsAT	p.Ala153Ile	missense_variant		1		ENSP00000255531.7
PCDH19	ENST00000420881.6	c.457_458delGCinsAT	p.Ala153Ile	missense_variant		1		ENSP00000400327.2

Frequencies

GnomAD3 genomes Cov.: 24

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

GnomAD4 genome Cov.: 24

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Developmental and epileptic encephalopathy, 9 Pathogenic:1 Uncertain:1

Aug 10, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 216981). This missense change has been observed in individual(s) with clinical features of developmental and epileptic encephalopathy (PMID: 25326637). Information on the frequency of this variant in the gnomAD database is not available, as this variant may be reported differently in the database. This sequence change replaces alanine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 153 of the PCDH19 protein (p.Ala153Ile). -

Aug 12, 2014

UCLA Clinical Genomics Center, UCLA

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs863224907; hg19: chrX-99663138;