rs869312851

Positions:

• chrX-18588077-GCTAGGACCACTTC-GGATCGTGGAA

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PM4_Supporting PP3

The NM_001323289.2(CDKL5):​c.679_691delCTAGGACCACTTCinsGATCGTGGAA​(p.Leu227_Pro231delinsAspArgGlyThr) variant causes a missense, disruptive inframe deletion 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 Uncertain significance (no stars).

• Frequency: Genomes: not found (cov: 22)
• Consequence: CDKL5 NM_001323289.2 missense, disruptive_inframe_deletion
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 7.74

Genes affected

CDKL5 (HGNC:11411): (cyclin dependent kinase like 5) This gene is a member of Ser/Thr protein kinase family and encodes a phosphorylated protein with protein kinase activity. Mutations in this gene have been associated with X-linked infantile spasm syndrome (ISSX), also known as X-linked West syndrome, and Rett syndrome (RTT). Alternate transcriptional splice variants have been characterized. [provided by RefSeq, Jul 2008]

CDKL5 (HGNC:):

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_001323289.2. Strenght limited to Supporting due to length of the change: 1aa.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDKL5	NM_001323289.2	c.679_691delCTAGGACCACTTCinsGATCGTGGAA	p.Leu227_Pro231delinsAspArgGlyThr	missense_variant, disruptive_inframe_deletion		ENST00000623535.2	NP_001310218.1
CDKL5	NM_001037343.2	c.679_691delCTAGGACCACTTCinsGATCGTGGAA	p.Leu227_Pro231delinsAspArgGlyThr	missense_variant, disruptive_inframe_deletion			NP_001032420.1
CDKL5	NM_003159.3	c.679_691delCTAGGACCACTTCinsGATCGTGGAA	p.Leu227_Pro231delinsAspArgGlyThr	missense_variant, disruptive_inframe_deletion			NP_003150.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDKL5	ENST00000623535.2	c.679_691delCTAGGACCACTTCinsGATCGTGGAA	p.Leu227_Pro231delinsAspArgGlyThr	missense_variant, disruptive_inframe_deletion		1	NM_001323289.2	ENSP00000485244.1

Frequencies

GnomAD3 genomes Cov.: 22

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

GnomAD4 genome Cov.: 22

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

Developmental and epileptic encephalopathy, 2 Uncertain:1

Uncertain significance, no assertion criteria provided

curation

RettBASE

Mar 13, 2014

This mutation is the deletion of c.678_691, replaced with the inversion of c.673_683; open-reading frame stays the same -

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: rs869312851; hg19: chrX-18606198;