X-100296287-A-ATATCCT

Variant summary

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

The NM_001184880.2(PCDH19):c.3436_3437insAGGATA(p.Lys1144_Asp1145dup) variant causes a inframe insertion 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 inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.62

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: Nonframeshift variant in NON repetitive region in NM_001184880.2.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCDH19	NM_001184880.2	c.3436_3437insAGGATA	p.Lys1144_Asp1145dup	inframe_insertion	6/6	ENST00000373034.8
PCDH19	NM_001105243.2	c.3295_3296insAGGATA	p.Lys1097_Asp1098dup	inframe_insertion	5/5
PCDH19	NM_020766.3	c.3292_3293insAGGATA	p.Lys1096_Asp1097dup	inframe_insertion	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCDH19	ENST00000373034.8	c.3436_3437insAGGATA	p.Lys1144_Asp1145dup	inframe_insertion	6/6	1	NM_001184880.2	A1
PCDH19	ENST00000255531.8	c.3295_3296insAGGATA	p.Lys1097_Asp1098dup	inframe_insertion	5/5	1		P5
PCDH19	ENST00000420881.6	c.3292_3293insAGGATA	p.Lys1096_Asp1097dup	inframe_insertion	5/5	1		A1
PCDH19	ENST00000464981.1	c.13_14insAGGATA	p.Lys3_Asp4dup	inframe_insertion, 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

Dec 05, 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. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. ClinVar contains an entry for this variant (Variation ID: 955455). This variant has not been reported in the literature in individuals affected with PCDH19-related conditions. This variant is not present in population databases (gnomAD no frequency). This variant, c.3431_3436dup, results in the insertion of 2 amino acid(s) of the PCDH19 protein (p.Lys1144_Asp1145dup), but otherwise preserves the integrity of the reading frame. -

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: rs1924597346; hg19: chrX-99551285;