rs267608429

chrX-18564502-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PP3_Moderate PP5_Moderate

The NM_001323289.2(CDKL5):c.125A>G(p.Lys42Arg) variant causes a missense change. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as 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 criteria provided, single submitter P:2
• 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 Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_001323289.2
• 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 [Pathogenic]. Clinvar id is 143772.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDKL5	NM_001323289.2	c.125A>G	p.Lys42Arg	missense_variant	4/18	ENST00000623535.2
CDKL5	NM_001037343.2	c.125A>G	p.Lys42Arg	missense_variant	5/22
CDKL5	NM_003159.3	c.125A>G	p.Lys42Arg	missense_variant	4/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDKL5	ENST00000623535.2	c.125A>G	p.Lys42Arg	missense_variant	4/18	1	NM_001323289.2	P1

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

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Developmental and epileptic encephalopathy, 2 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Feb 08, 2013

- -

not provided Pathogenic:1

Pathogenic, no assertion criteria provided

research

RettBASE

Feb 15, 2011

- -

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
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
MutationTaster	Benign	1.0	D;D
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;