rs757573258

chrX-18604655-G-AchrX-18604655-G-T

Variant summary

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

The NM_001323289.2(CDKL5):c.1731G>A(p.Met577Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict 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. M577T) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 23)
• Consequence: CDKL5 NM_001323289.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.34

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=0.09862721).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDKL5	NM_001323289.2	c.1731G>A	p.Met577Ile	missense_variant	12/18	ENST00000623535.2
CDKL5	NM_001037343.2	c.1731G>A	p.Met577Ile	missense_variant	13/22
CDKL5	NM_003159.3	c.1731G>A	p.Met577Ile	missense_variant	12/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDKL5	ENST00000623535.2	c.1731G>A	p.Met577Ile	missense_variant	12/18	1	NM_001323289.2	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 23

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

May 21, 2019

In summary, this variant is a novel missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The isoleucine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a CDKL5-related disease. This sequence change replaces methionine with isoleucine at codon 577 of the CDKL5 protein (p.Met577Ile). The methionine residue is highly conserved and there is a small physicochemical difference between methionine and isoleucine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.63
Cadd	Benign	18
Dann	Uncertain	0.98
DEOGEN2	Benign	0.030	T;T;T;.;.
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.099	T;T;T;T;T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	0.69	N;.;N;.;N
MutationTaster	Benign	0.81	N;N
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.72	N;.;N;.;.
REVEL	Benign	0.16
Sift	Uncertain	0.0090	D;.;D;.;.
Sift4G	Benign	0.16	T;.;T;T;T
Polyphen		0.0	B;.;B;.;.
Vest4		0.17
MutPred		0.049		Gain of glycosylation at S580 (P = 0.0828);Gain of glycosylation at S580 (P = 0.0828);Gain of glycosylation at S580 (P = 0.0828);Gain of glycosylation at S580 (P = 0.0828);Gain of glycosylation at S580 (P = 0.0828);
MVP		0.48
MPC		0.38
ClinPred		0.31	T
GERP RS		4.2
Varity_R		0.39
gMVP		0.11

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs757573258; hg19: chrX-18622775;