X-18604602-A-G

Position:

• chrX-18604602-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.1678A>G​(p.Thr560Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00000455 in 1,098,206 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000046 (0 hom. 1 hem.)
• Consequence: CDKL5 NM_001323289.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 4.49

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=0.11430299).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDKL5	NM_001323289.2	c.1678A>G	p.Thr560Ala	missense_variant	12/18	ENST00000623535.2	NP_001310218.1
CDKL5	NM_001037343.2	c.1678A>G	p.Thr560Ala	missense_variant	13/22		NP_001032420.1
CDKL5	NM_003159.3	c.1678A>G	p.Thr560Ala	missense_variant	12/21		NP_003150.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDKL5	ENST00000623535.2	c.1678A>G	p.Thr560Ala	missense_variant	12/18	1	NM_001323289.2	ENSP00000485244	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD3 exomes AF: 0.00000546 AC: 1 AN: 183276 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 67768

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000122

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000455 AC: 5 AN: 1098206 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 1 AN XY: 363560

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: 0.00000594

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

Bravo AF: 0.00000756

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Developmental and epileptic encephalopathy, 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Feb 08, 2013

- -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 17, 2023

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. 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 not expected to disrupt CDKL5 protein function. ClinVar contains an entry for this variant (Variation ID: 158180). This variant has not been reported in the literature in individuals affected with CDKL5-related conditions. This variant is present in population databases (rs587783400, gnomAD 0.001%). This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 560 of the CDKL5 protein (p.Thr560Ala). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Benign	0.030	T;T;T;.;.
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.83	.;T;T;T;T
M_CAP	Uncertain	0.091	D
MetaRNN	Benign	0.11	T;T;T;T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.69	N;.;N;.;N
MutationTaster	Benign	0.96	N;N
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.0	N;.;N;.;.
REVEL	Benign	0.13
Sift	Benign	0.055	T;.;T;.;.
Sift4G	Benign	0.70	T;.;T;T;T
Polyphen		0.43	B;.;B;.;.
Vest4		0.32
MutPred		0.099		Loss of phosphorylation at T560 (P = 0.0176);Loss of phosphorylation at T560 (P = 0.0176);Loss of phosphorylation at T560 (P = 0.0176);Loss of phosphorylation at T560 (P = 0.0176);Loss of phosphorylation at T560 (P = 0.0176);
MVP		0.79
MPC		0.47
ClinPred		0.35	T
GERP RS		4.7
Varity_R		0.21
gMVP		0.17

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: rs587783400; hg19: chrX-18622722;