rs122460158

Variant names:

• chrX-18628374-C-T
• rs122460158
• NM_001323289.2:c.2500C>T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM6 PVS1 PM2_Supporting PP4

This summary comes from the ClinGen Evidence Repository: The p.Gln834Ter variant in CDKL5 is predicted to cause a premature stop codon that leads to a truncated or absent protein in a gene where loss-of-function is an established mechanism. There is significant evidence that loss of this region of the gene is pathogenic (PVS1). The p.Gln834Ter variant in CDKL5 is absent from gnomAD v4.1 (PM2_Supporting). The p.Gln834Ter variant in CDKL5 has been reported in an individual with a clinical phenotype suggestive of CDKL5 disorder (PMID:16813600) (PP4). The p.Gln834Ter variant in CDKL5 occurs in the de novo state (biological parentage unconfirmed) in this individual (PM6). In summary, the p.Gln834Ter variant in CDKL5 is classified as Pathogenic for CDKL5 disorder based on the ACMG/AMP criteria (PVS1, PM2_Supporting, PP4, PM6). LINK:https://erepo.genome.network/evrepo/ui/classification/CA121519/MONDO:0100039/034

• Frequency: Genomes: not found (cov: 23)
• Consequence: CDKL5 NM_001323289.2 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:5 U:1
• Conservation: PhyloP100: 7.38
• Publications: 7 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 12 ACMG points.

• PVS1: 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.
• PP4: 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.2500C>T	p.Gln834*	stop_gained	Exon 18 of 18	NP_001310218.1	O76039-2
	CDKL5	NM_001037343.2		c.2500C>T	p.Gln834*	stop_gained	Exon 19 of 22	NP_001032420.1	O76039-1
	CDKL5	NM_003159.3		c.2500C>T	p.Gln834*	stop_gained	Exon 18 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.2500C>T	p.Gln834*	stop_gained	Exon 18 of 18	ENSP00000485244.1	O76039-2
	CDKL5	ENST00000379989.6	TSL:1	c.2500C>T	p.Gln834*	stop_gained	Exon 19 of 22	ENSP00000369325.3	O76039-1
	CDKL5	ENST00000379996.7	TSL:1	c.2500C>T	p.Gln834*	stop_gained	Exon 18 of 21	ENSP00000369332.3	O76039-1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
2	-	-	CDKL5 disorder (2)
1	1	-	Developmental and epileptic encephalopathy, 2 (2)
1	-	-	Atypical Rett syndrome (1)
1	-	-	Developmental and epileptic encephalopathy, 2;CN128785:Angelman syndrome-like (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.66
CADD	Pathogenic	37
DANN	Uncertain	1.0
FATHMM_MKL	Pathogenic	1.0	D
PhyloP100		7.4
Vest4		0.98
GERP RS		5.7
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.19		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: rs122460158; hg19: chrX-18646494;