X-18507155-G-T

Variant names:

• chrX-18507155-G-T
• rs786204962
• NM_001323289.2:c.59G>T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PP3 PM2_Supporting PM1 PM5_Strong PS2

This summary comes from the ClinGen Evidence Repository: The p.Gly20Val variant in CDKL5 occurs in the de novo state (biological parentage confirmed) in this individual (PS2). Multiple pathogenic missense variants have been previously identified within this codon which indicates that this residue is critical to the function of the protein (PMID 23064044, 20397747) (PM5_Strong). The p.Gly20Val variant in CDKL5 is absent from gnomAD (PM2_Supporting). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). In summary, the p.Gly20Val variant in CDKL5 is classified as pathogenic for CDKL5-associated disorder based on the ACMG/AMP criteria (PS2, PM5_strong, PM2_supporting, PP3). LINK:https://erepo.genome.network/evrepo/ui/classification/CA412489610/MONDO:0100039/016

• Frequency: Genomes: not found (cov: 23)
• Consequence: CDKL5 NM_001323289.2 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:2 O:1
• Conservation: PhyloP100: 8.37
• Publications: 2 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.

• PS2: For more information check the summary or visit ClinGen Evidence Repository.
• PM1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM5: 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDKL5	NM_001323289.2	MANE Select	c.59G>T	p.Gly20Val	missense	Exon 2 of 18	NP_001310218.1
	CDKL5	NM_001037343.2		c.59G>T	p.Gly20Val	missense	Exon 3 of 22	NP_001032420.1
	CDKL5	NM_003159.3		c.59G>T	p.Gly20Val	missense	Exon 2 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.59G>T	p.Gly20Val	missense	Exon 2 of 18	ENSP00000485244.1
	CDKL5	ENST00000379989.6	TSL:1	c.59G>T	p.Gly20Val	missense	Exon 3 of 22	ENSP00000369325.3
	CDKL5	ENST00000379996.7	TSL:1	c.59G>T	p.Gly20Val	missense	Exon 2 of 21	ENSP00000369332.3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 25

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

CDKL5 disorder Pathogenic:1

Mar 26, 2021

ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The p.Gly20Val variant in CDKL5 occurs in the de novo state (biological parentage confirmed) in this individual (PS2). Multiple pathogenic missense variants have been previously identified within this codon which indicates that this residue is critical to the function of the protein (PMID 23064044, 20397747) (PM5_Strong). The p.Gly20Val variant in CDKL5 is absent from gnomAD (PM2_Supporting). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). In summary, the p.Gly20Val variant in CDKL5 is classified as pathogenic for CDKL5-associated disorder based on the ACMG/AMP criteria (PS2, PM5_strong, PM2_supporting, PP3).

not provided Pathogenic:1

Jan 08, 2019

Genetic Services Laboratory, University of Chicago

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

DNA sequence analysis of the CDKL5 gene demonstrated a sequence change, c.59G>T, in the apparent heterozygous state in an affected male individual, in exon 2 that results in an amino acid change, p.Gly20Val. This sequence change does not appear to have been previously described in patients with CDKL5-related disorders and has also not been described as a known benign sequence change in the CDKL5 gene. However, different pathogenic sequence changes affecting the same amino acid residue (p.Gly20Arg and p.Gly20Asp) have been described in patients with epileptic encephalopathy (White et al., 2010; Raymond et al., 2013). The p.Gly20Val change affects a highly conserved amino acid residue located in the ATP-binding domain of the CDKL5 protein where other missense pathogenic changes have been described. The presence of the c.59G>T (p.Gly20Val) variant in the apparent heterozygous state in this male patient is indicative of it having risen somatically and being in the mosaic state. This variant was seen to be present in approximately 27% of reads by next generation sequencing. Sanger sequencing confirmed the presence of this variant with the variant allele peak being a lot smaller than the normal allele peak on the sequence chromatogram, supporting the next generation sequencing finding. This sequence change is likely pathogenic; however functional studies have not been performed to prove this conclusively.

Developmental and epileptic encephalopathy, 2 Other:1

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant classified as Likely pathogenic and reported on 01-11-2019 by University of Chicago. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.31	T
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.96	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.90	D
MutationAssessor	Pathogenic	4.7	H
PhyloP100		8.4
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-6.8	D
REVEL	Pathogenic	0.93
Sift	Uncertain	0.0020	D
Sift4G	Benign	0.12	T
Polyphen		1.0	D
Vest4		0.97
MutPred		0.90		Loss of sheet (P = 0.1158)
MVP		0.99
MPC		2.9
ClinPred		1.0	D
GERP RS		4.7
Varity_R		0.99
gMVP		0.97
Mutation Taster		=5/95	disease causing

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: rs786204962; hg19: chrX-18525275;