rs1555952013

Variant names:

• chrX-18604268-G-A
• rs1555952013
• NM_001323289.2:c.1344G>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4 BP6

The NM_001323289.2(CDKL5):​c.1344G>A​(p.Met448Ile) 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M448V) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 23)
• Consequence: CDKL5 NM_001323289.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 5.02

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=0.2886551).
• BP6: Variant X-18604268-G-A is Benign according to our data. Variant chrX-18604268-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 547186.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDKL5	NM_001323289.2	c.1344G>A	p.Met448Ile	missense_variant	Exon 12 of 18	ENST00000623535.2	NP_001310218.1
CDKL5	NM_001037343.2	c.1344G>A	p.Met448Ile	missense_variant	Exon 13 of 22		NP_001032420.1
CDKL5	NM_003159.3	c.1344G>A	p.Met448Ile	missense_variant	Exon 12 of 21		NP_003150.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDKL5	ENST00000623535.2	c.1344G>A	p.Met448Ile	missense_variant	Exon 12 of 18	1	NM_001323289.2	ENSP00000485244.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 23

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Oct 21, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has not been reported in the literature in individuals affected with CDKL5-related conditions. ClinVar contains an entry for this variant (Variation ID: 547186). 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. 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. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 448 of the CDKL5 protein (p.Met448Ile). -

West syndrome Benign:1

Nov 01, 2016

Center for Human Genetics, Inc, Center for Human Genetics, Inc

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.036	T;T;.;T;.;.
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.84	.;T;T;T;T;T
M_CAP	Pathogenic	0.65	D
MetaRNN	Benign	0.29	T;T;T;T;T;T
MetaSVM	Benign	-0.73	T
MutationAssessor	Benign	1.8	L;.;.;L;.;L
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-0.88	N;.;.;N;.;.
REVEL	Benign	0.079
Sift	Uncertain	0.0040	D;.;.;D;.;.
Sift4G	Benign	0.18	T;.;.;T;T;T
Polyphen		0.013	B;.;.;B;.;.
Vest4		0.53
MutPred		0.11		Loss of MoRF binding (P = 0.0933);Loss of MoRF binding (P = 0.0933);Loss of MoRF binding (P = 0.0933);Loss of MoRF binding (P = 0.0933);Loss of MoRF binding (P = 0.0933);Loss of MoRF binding (P = 0.0933);
MVP		0.77
MPC		0.39
ClinPred		0.86	D
GERP RS		5.2
Varity_R		0.78
gMVP		0.11

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: rs1555952013; hg19: chrX-18622388;