chrX-18609570-G-A

Variant names:

• chrX-18609570-G-A
• rs267608653
• NM_001323289.2:c.2152G>A

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PS3_Supporting PM2_Supporting PM6_Strong PP4 PS4

This summary comes from the ClinGen Evidence Repository: The p.Val718Met variant in CDKL5 has been reported in at least 2 de novo occurrences (biological parentage unconfirmed) in individuals with a CDKL5-related disorder (PMID 18790821, 27599155) (PM6_strong). The p.Val718Met variant has been observed at least 5 individuals with CDKL5-related disorders (PMID 31313283, 18790821, 27599155, GeneDx internal database) (PS4), including in an individual with a clinical phenotype very specific to a CDKL5-related disorder (PMID 27599155) (PP4). Additionally, an in vitro study using a minigene splicing assay showed that splicing is disrupted, resulting in exon 14 being omitted from the transcript (PMID:29264392) (PS3_supporting). The p.Val718Met variant in CDKL5 is absent from gnomAD v4.1 (PM2_Supporting). In summary, the p.Val718Met variant in CDKL5 is classified as pathogenic for CDKL5-related disorders based on the ACMG/AMP criteria (PM6_strong, PS4, PP4, PS3_supporting, PM2_supporting). (CDKL5 Specifications v.4.1; curation approved on [5/7/2025]) LINK:https://erepo.genome.network/evrepo/ui/classification/CA199279/MONDO:0100039/034

• Frequency: Genomes: not found (cov: 23)
• Consequence: CDKL5 NM_001323289.2 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic reviewed by expert panel P:3 U:1
• Conservation: PhyloP100: 9.33
• Publications: 10 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 11 ACMG points.

• PS3: 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.
• 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDKL5	NM_001323289.2	MANE Select	c.2152G>A	p.Val718Met	missense splice_region	Exon 14 of 18	NP_001310218.1
	CDKL5	NM_001037343.2		c.2152G>A	p.Val718Met	missense splice_region	Exon 15 of 22	NP_001032420.1
	CDKL5	NM_003159.3		c.2152G>A	p.Val718Met	missense splice_region	Exon 14 of 21	NP_003150.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDKL5	ENST00000623535.2	TSL:1 MANE Select	c.2152G>A	p.Val718Met	missense splice_region	Exon 14 of 18	ENSP00000485244.1
	CDKL5	ENST00000379989.6	TSL:1	c.2152G>A	p.Val718Met	missense splice_region	Exon 15 of 22	ENSP00000369325.3
	CDKL5	ENST00000379996.7	TSL:1	c.2152G>A	p.Val718Met	missense splice_region	Exon 14 of 21	ENSP00000369332.3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

CDKL5 disorder Pathogenic:1 Uncertain:1

Sep 16, 2024

Centre for Population Genomics, CPG

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

This variant has been collected from RettBASE and curated to current modified ACMG/AMP criteria. Based on the classification scheme defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like Disorders Specifications to the ACMG/AMP Variant Interpretation Guidelines VCEP 3.0, this variant is classified as a variant of uncertain significance. At least the following criteria are met: This variant has been identified as a de novo occurrence in an individual with CDKL5 disorder without confirmation of paternity and maternity (PM6, PMID: 18790821). This variant is absent from gnomAD (PM2_Supporting).

May 07, 2025

ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The p.Val718Met variant in CDKL5 has been reported in at least 2 de novo occurrences (biological parentage unconfirmed) in individuals with a CDKL5-related disorder (PMID 18790821, 27599155) (PM6_strong). The p.Val718Met variant has been observed at least 5 individuals with CDKL5-related disorders (PMID 31313283, 18790821, 27599155, GeneDx internal database) (PS4), including in an individual with a clinical phenotype very specific to a CDKL5-related disorder (PMID 27599155) (PP4). Additionally, an in vitro study using a minigene splicing assay showed that splicing is disrupted, resulting in exon 14 being omitted from the transcript (PMID: 29264392) (PS3_supporting). The p.Val718Met variant in CDKL5 is absent from gnomAD v4.1 (PM2_Supporting). In summary, the p.Val718Met variant in CDKL5 is classified as pathogenic for CDKL5-related disorders based on the ACMG/AMP criteria (PM6_strong, PS4, PP4, PS3_supporting, PM2_supporting). (CDKL5 Specifications v.4.1; curation approved on [5/7/2025])

Developmental and epileptic encephalopathy, 2 Pathogenic:1

Mar 13, 2014

RettBASE

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: curation

No parental studies; highly conserved residue; In silico prediction: SIFT = deleterious, MutationTaster = disease-causing, PolyPhen2 = probably damaging, AlignGVGD = benign (C0)

not provided Pathogenic:1

Mar 19, 2014

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The V718M missense mutation in the CDKL5 gene has been reported previously as a de novo mutation in a patient with infantile spasms, microcephaly with deceleration of head growth, severe intellectual disability, and limited hand skills (Bahi-Buisson et al., 2008). This mutation alters a highly conserved position in the C-terminal region of the protein. The variant is found in INFANT-EPI panel(s).

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.040	T
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.64	D
MetaRNN	Pathogenic	0.76	D
MetaSVM	Uncertain	0.23	D
MutationAssessor	Uncertain	2.0	M
PhyloP100		9.3
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-0.77	N
REVEL	Uncertain	0.63
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0050	D
Polyphen		1.0	D
Vest4		0.43
MutPred		0.65		Gain of MoRF binding (P = 0.1104)
MVP		0.96
MPC		0.77
ClinPred		0.94	D
GERP RS		5.8
Varity_R		0.66
gMVP		0.35
Mutation Taster		=11/89	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.32		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.32		Position offset: 0

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

Other links and lift over

dbSNP: rs267608653; hg19: chrX-18627690;