X-100296286-G-GAT

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PM4

The NM_001184880.2(PCDH19):c.3437_3438insAT(p.Val1147SerfsTer50) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: PCDH19 NM_001184880.2 frameshift
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.92

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Frameshift in the end of transcript resulting in stoplost. Downstream stopcodon found after 1153 codons.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCDH19	NM_001184880.2	c.3437_3438insAT	p.Val1147SerfsTer50	frameshift_variant	6/6	ENST00000373034.8
PCDH19	NM_001105243.2	c.3296_3297insAT	p.Val1100SerfsTer50	frameshift_variant	5/5
PCDH19	NM_020766.3	c.3293_3294insAT	p.Val1099SerfsTer50	frameshift_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCDH19	ENST00000373034.8	c.3437_3438insAT	p.Val1147SerfsTer50	frameshift_variant	6/6	1	NM_001184880.2	A1
PCDH19	ENST00000255531.8	c.3296_3297insAT	p.Val1100SerfsTer50	frameshift_variant	5/5	1		P5
PCDH19	ENST00000420881.6	c.3293_3294insAT	p.Val1099SerfsTer50	frameshift_variant	5/5	1		A1
PCDH19	ENST00000464981.1	c.14_15insAT	p.Val6SerfsTer33	frameshift_variant, NMD_transcript_variant	1/2	3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Developmental and epileptic encephalopathy, 9 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jun 16, 2021

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. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This variant has been observed in individual(s) with clinical features of early infantile epileptic encephalopathy (Invitae). This variant is not present in population databases (ExAC no frequency). This sequence change results in a frameshift in the PCDH19 gene (p.Val1147Serfs*50). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 2 amino acids of the PCDH19 protein and extend the protein by an additional 47 amino acids. -

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: rs1924597176; hg19: chrX-99551284;