rs786204967

Variant names:

• chrX-18604168-CAG-C
• rs786204967
• NM_001323289.2:c.1247_1248delAG

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PVS1 PM6_Strong PM2_Supporting PS4

This summary comes from the ClinGen Evidence Repository: The p.Glu416Valfs variant in CDKL5 is predicted to cause a premature stop codon that leads to a truncated or absent protein in a gene in which loss-of-function is an established mechanism. There is significant evidence that loss of this region of the gene is pathogenic (PVS1). The p.Glu416Valfs variant has been observed in at least 5 individuals with CDKL5 disease (PMID:27779742, 27864847, 23064044, ClinVar Variation ID 189554) (PS4). The p.XX variant in GENE has been reported in at least 2 de novo occurrences (biological parentage unconfirmed) in individuals with CDKL5 disorder (PMID XX) (PMID 27779742, 27864847) (PM6_strong). This variant is absent from gnomAD (PM2_supporting). In summary, this variant meets criteria to be classified as pathogenic for CDKL5-associated disorder based on the ACMG/AMP criteria applied (PVS1, PS4, PM6_strong, PM2_supporting). LINK:https://erepo.genome.network/evrepo/ui/classification/CA235608/MONDO:0100039/016

• Frequency: Genomes: not found (cov: 23)
• Consequence: CDKL5 NM_001323289.2 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:8
• Conservation: PhyloP100: 9.60
• Publications: 3 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: Pathogenic. The variant received 17 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM6: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001323289.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDKL5	NM_001323289.2	MANE Select	c.1247_1248delAG	p.Glu416ValfsTer2	frameshift	Exon 12 of 18	NP_001310218.1	O76039-2
	CDKL5	NM_001037343.2		c.1247_1248delAG	p.Glu416ValfsTer2	frameshift	Exon 13 of 22	NP_001032420.1	O76039-1
	CDKL5	NM_003159.3		c.1247_1248delAG	p.Glu416ValfsTer2	frameshift	Exon 12 of 21	NP_003150.1	O76039-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDKL5	ENST00000623535.2	TSL:1 MANE Select	c.1247_1248delAG	p.Glu416ValfsTer2	frameshift	Exon 12 of 18	ENSP00000485244.1	O76039-2
	CDKL5	ENST00000379989.6	TSL:1	c.1247_1248delAG	p.Glu416ValfsTer2	frameshift	Exon 13 of 22	ENSP00000369325.3	O76039-1
	CDKL5	ENST00000379996.7	TSL:1	c.1247_1248delAG	p.Glu416ValfsTer2	frameshift	Exon 12 of 21	ENSP00000369332.3	O76039-1

Frequencies

GnomAD3 genomes Cov.: 23

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

GnomAD4 genome Cov.: 23

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
2	-	-	CDKL5 disorder (2)
2	-	-	not provided (2)
1	-	-	Developmental and epileptic encephalopathy, 2 (1)
1	-	-	Developmental and epileptic encephalopathy, 2;CN128785:Angelman syndrome-like (1)
1	-	-	Epileptic encephalopathy (1)
1	-	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.6
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs786204967; hg19: chrX-18622288;