X-18575384-G-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Moderate

The NM_001323289.2(CDKL5):c.176G>C(p.Arg59Pro) variant causes a missense change involving the alteration of a conserved nucleotide. 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R59Q) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 23)
• Consequence: CDKL5 NM_001323289.2 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 10.0

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 12 ACMG points.

• PM1: In a domain Protein kinase (size 284) in uniprot entity CDKL5_HUMAN there are 132 pathogenic changes around while only 4 benign (97%) in NM_001323289.2
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-18575384-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 496681.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.983
• PP5: Variant X-18575384-G-C is Pathogenic according to our data. Variant chrX-18575384-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 495231.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-18575384-G-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDKL5	NM_001323289.2	c.176G>C	p.Arg59Pro	missense_variant	5/18	ENST00000623535.2
CDKL5	NM_001037343.2	c.176G>C	p.Arg59Pro	missense_variant	6/22
CDKL5	NM_003159.3	c.176G>C	p.Arg59Pro	missense_variant	5/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDKL5	ENST00000623535.2	c.176G>C	p.Arg59Pro	missense_variant	5/18	1	NM_001323289.2	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 23

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Developmental and epileptic encephalopathy, 2 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

NeuroMeGen, Hospital Clinico Santiago de Compostela

Jan 01, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.36
Cadd	Pathogenic	33
Dann	Uncertain	1.0
DEOGEN2	Benign	0.25	T;T;.;T;.;.;.;.
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.97	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.095	D
MutationAssessor	Pathogenic	3.6	H;.;.;H;.;.;.;H
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-6.7	D;.;.;D;.;.;.;.
REVEL	Pathogenic	0.74
Sift	Pathogenic	0.0	D;.;.;D;.;.;.;.
Sift4G	Pathogenic	0.0	D;.;.;D;D;D;D;D
Polyphen		1.0	D;.;.;D;.;.;.;.
Vest4		0.99
MutPred		0.90		Loss of MoRF binding (P = 0.018);Loss of MoRF binding (P = 0.018);Loss of MoRF binding (P = 0.018);Loss of MoRF binding (P = 0.018);Loss of MoRF binding (P = 0.018);Loss of MoRF binding (P = 0.018);Loss of MoRF binding (P = 0.018);Loss of MoRF binding (P = 0.018);
MVP		0.95
MPC		3.1
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.99
gMVP		1.0

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: rs1555949009; hg19: chrX-18593504;