X-18507112-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001323289.2(CDKL5):c.16A>G(p.Ile6Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I6T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 23)
• Consequence: CDKL5 NM_001323289.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.69

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18941656).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDKL5	NM_001323289.2	c.16A>G	p.Ile6Val	missense_variant	2/18	ENST00000623535.2
CDKL5	NM_001037343.2	c.16A>G	p.Ile6Val	missense_variant	3/22
CDKL5	NM_003159.3	c.16A>G	p.Ile6Val	missense_variant	2/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDKL5	ENST00000623535.2	c.16A>G	p.Ile6Val	missense_variant	2/18	1	NM_001323289.2	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 26

GnomAD4 genome Cov.: 23

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Developmental and epileptic encephalopathy, 2;CN128785:Angelman syndrome-like Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 13, 2023

This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 6 of the CDKL5 protein (p.Ile6Val). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with CDKL5-related conditions. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CDKL5 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.080	T
BayesDel_noAF	Benign	-0.35
Cadd	Benign	22
Dann	Uncertain	0.99
DEOGEN2	Benign	0.021	T;T;.;T;T;.;.;.;.
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Pathogenic	0.34	D
MetaRNN	Benign	0.19	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	0.17	N;.;.;N;.;.;.;.;N
MutationTaster	Benign	0.73	N;N
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-0.20	N;.;.;N;.;.;.;.;.
REVEL	Benign	0.18
Sift	Uncertain	0.0030	D;.;.;D;.;.;.;.;.
Sift4G	Uncertain	0.029	D;.;.;D;.;T;T;T;T
Polyphen		0.51	P;.;.;P;.;.;.;.;.
Vest4		0.29
MutPred		0.30		Loss of methylation at K2 (P = 0.101);Loss of methylation at K2 (P = 0.101);Loss of methylation at K2 (P = 0.101);Loss of methylation at K2 (P = 0.101);Loss of methylation at K2 (P = 0.101);Loss of methylation at K2 (P = 0.101);Loss of methylation at K2 (P = 0.101);Loss of methylation at K2 (P = 0.101);Loss of methylation at K2 (P = 0.101);
MVP		0.75
MPC		1.2
ClinPred		0.57	D
GERP RS		5.4
Varity_R		0.22
gMVP		0.64

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1922604127; hg19: chrX-18525232;