rs267608429

Variant names:

• chrX-18564502-A-G
• rs267608429
• NM_001323289.2:c.125A>G

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PP3_Moderate PP5_Very_Strong

The NM_001323289.2(CDKL5):​c.125A>G​(p.Lys42Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 21)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: CDKL5 NM_001323289.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 4.01

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]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM1: In a binding_site (size 0) in uniprot entity CDKL5_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.905
• PP5: Variant X-18564502-A-G is Pathogenic according to our data. Variant chrX-18564502-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 143772.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDKL5	NM_001323289.2	c.125A>G	p.Lys42Arg	missense_variant	Exon 4 of 18	ENST00000623535.2	NP_001310218.1
CDKL5	NM_001037343.2	c.125A>G	p.Lys42Arg	missense_variant	Exon 5 of 22		NP_001032420.1
CDKL5	NM_003159.3	c.125A>G	p.Lys42Arg	missense_variant	Exon 4 of 21		NP_003150.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDKL5	ENST00000623535.2	c.125A>G	p.Lys42Arg	missense_variant	Exon 4 of 18	1	NM_001323289.2	ENSP00000485244.1

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 987881 Hom.: 0 Cov.: 18 AF XY: 0.00 AC XY: 0 AN XY: 279289

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 21

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Developmental and epileptic encephalopathy, 2 Pathogenic:1

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

CDKL5 disorder Pathogenic:1

Jul 11, 2024

Centre for Population Genomics, CPG

Significance: Likely pathogenic

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 likely pathogenic. At least the following criteria are met: This variant is absent from gnomAD v4 (PM2_Supporting). Computational prediction analysis tools suggests a deleterious impact (REVEL score>= 0.75) (PP3). Occurs in the well-characterized ATP binding region of CDKL5 (PM1). Well-established in vitro or in vivo functional studies supportive of a damaging effect on the protein function (PS3). PMID: 29474534, PMID:20861382 , PMID:16935860 -

not provided Pathogenic:1

Feb 15, 2011

RettBASE

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.19	T;T;.;T;.;.;.;.
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	1.0	.;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.87	D
MetaRNN	Pathogenic	0.91	D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.79	D
MutationAssessor	Pathogenic	3.5	M;.;.;M;.;.;.;M
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-2.7	D;.;.;D;.;.;.;.
REVEL	Pathogenic	0.83
Sift	Uncertain	0.0010	D;.;.;D;.;.;.;.
Sift4G	Pathogenic	0.0	D;.;.;D;D;D;D;D
Polyphen		0.99	D;.;.;D;.;.;.;.
Vest4		0.77
MutPred		0.71		Loss of methylation at K42 (P = 8e-04);Loss of methylation at K42 (P = 8e-04);Loss of methylation at K42 (P = 8e-04);Loss of methylation at K42 (P = 8e-04);Loss of methylation at K42 (P = 8e-04);Loss of methylation at K42 (P = 8e-04);Loss of methylation at K42 (P = 8e-04);Loss of methylation at K42 (P = 8e-04);
MVP		0.97
MPC		2.3
ClinPred		0.99	D
GERP RS		4.8
Varity_R		0.94
gMVP		0.99

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

Publications

LitVar

Other links and lift over

dbSNP: rs267608429; hg19: chrX-18582622;