NM_001323289.2:c.199C>T

Variant names:

• chrX-18575407-C-T
• rs267608437
• NM_001323289.2:c.199C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2_Supporting PP3

This summary comes from the ClinGen Evidence Repository: The p.Leu67Phe variant in CDKL5 is absent from gnomAD v4.1 (PM2_Supporting). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). The p.Leu67Phe variant is not currently published and is not present in additional databases (internal and publicly available), therefore, no additional criteria are applicable at this time. In summary, the p.Leu67Phe variant in CDKL5 is classified as a variant of uncertain significance based on the ACMG/AMP criteria (PM2_supporting, PP3). (CDKL5 Specifications v.4.1; curation approved on [5/7/2025]) LINK:https://erepo.genome.network/evrepo/ui/classification/CA170464/MONDO:0100039/034

• Frequency: Genomes: not found (cov: 23)
• Consequence: CDKL5 NM_001323289.2 missense
• Clinical Significance: Uncertain significance reviewed by expert panel P:2 U:3
• Conservation: PhyloP100: 4.95
• Publications: 1 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: 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.199C>T	p.Leu67Phe	missense	Exon 5 of 18	NP_001310218.1	O76039-2
	CDKL5	NM_001037343.2		c.199C>T	p.Leu67Phe	missense	Exon 6 of 22	NP_001032420.1	O76039-1
	CDKL5	NM_003159.3		c.199C>T	p.Leu67Phe	missense	Exon 5 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.199C>T	p.Leu67Phe	missense	Exon 5 of 18	ENSP00000485244.1	O76039-2
	CDKL5	ENST00000379989.6	TSL:1	c.199C>T	p.Leu67Phe	missense	Exon 6 of 22	ENSP00000369325.3	O76039-1
	CDKL5	ENST00000379996.7	TSL:1	c.199C>T	p.Leu67Phe	missense	Exon 5 of 21	ENSP00000369332.3	O76039-1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: reviewed by expert panel

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.27
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.20	T
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.92	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Uncertain	0.049	D
MutationAssessor	Benign	2.0	M
PhyloP100		5.0
PrimateAI	Pathogenic	0.92	D
PROVEAN	Uncertain	-3.7	D
REVEL	Pathogenic	0.68
Sift	Uncertain	0.020	D
Sift4G	Uncertain	0.013	D
Polyphen		1.0	D
Vest4		0.78
MutPred		0.76		Gain of methylation at K68 (P = 0.0748)
MVP		0.95
MPC		2.6
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.92
gMVP		0.95
Mutation Taster		=24/76	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: rs267608437; hg19: chrX-18593527;