NM_001323289.2:c.679_691delCTAGGACCACTTCinsGATCGTGGAA

Variant names:

• chrX-18588078-CTAGGACCACTTC-GATCGTGGAA
• rs869312851
• NM_001323289.2:c.679_691delCTAGGACCACTTCinsGATCGTGGAA

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1 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). Synonymous variant affecting the same amino acid position (i.e. L227L) has been classified as Likely benign.

• 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
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• CDKL5 disorder

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
• developmental and epileptic encephalopathy, 2

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• atypical Rett syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• genetic developmental and epileptic encephalopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• infantile spasms

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• precocious puberty

  Inheritance: XL Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_001323289.2
• 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 rank	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 rank	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

Mar 13, 2014

RettBASE

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: curation

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

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.7
Mutation Taster		=1/199	disease causing (long InDel)

Splicing

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

Other links and lift over

dbSNP: rs869312851; hg19: chrX-18606198;