X-18588055-A-G

Variant names:

• chrX-18588055-A-G
• NM_001323289.2:c.656A>G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001323289.2(CDKL5):​c.656A>G​(p.Gln219Arg) 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 Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: CDKL5 NM_001323289.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 8.94

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.951

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDKL5	NM_001323289.2	c.656A>G	p.Gln219Arg	missense_variant	Exon 9 of 18	ENST00000623535.2	NP_001310218.1
CDKL5	NM_001037343.2	c.656A>G	p.Gln219Arg	missense_variant	Exon 10 of 22		NP_001032420.1
CDKL5	NM_003159.3	c.656A>G	p.Gln219Arg	missense_variant	Exon 9 of 21		NP_003150.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDKL5	ENST00000623535.2	c.656A>G	p.Gln219Arg	missense_variant	Exon 9 of 18	1	NM_001323289.2	ENSP00000485244.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 23

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

-

3billion

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is not observed in the gnomAD v2.1.1 dataset. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.70; 3Cnet: 0.99). A different missense change at the same codon (p.Gln219Pro) has been reported to be associated with CDKL5 related disorder (ClinVar ID: VCV000189549 / PMID: 23151060). However the evidence of pathogenicity is insufficient at this time. Therefore, this variant is classified as Uncertain significance according to the recommendation of ACMG/AMP guideline. -

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

Dec 24, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 expected to disrupt CDKL5 protein function. This variant has not been reported in the literature in individuals affected with CDKL5-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 219 of the CDKL5 protein (p.Gln219Arg). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.20	T;T;.;T;.;.
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.91	.;D;D;D;D;D
M_CAP	Pathogenic	0.76	D
MetaRNN	Pathogenic	0.95	D;D;D;D;D;D
MetaSVM	Benign	-0.30	T
MutationAssessor	Uncertain	2.4	M;.;.;M;.;M
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-4.0	D;.;.;D;.;.
REVEL	Pathogenic	0.70
Sift	Pathogenic	0.0	D;.;.;D;.;.
Sift4G	Pathogenic	0.0010	D;.;.;D;D;D
Polyphen		1.0	D;.;.;D;.;.
Vest4		0.96
MutPred		0.81		Gain of phosphorylation at T222 (P = 0.071);Gain of phosphorylation at T222 (P = 0.071);Gain of phosphorylation at T222 (P = 0.071);Gain of phosphorylation at T222 (P = 0.071);Gain of phosphorylation at T222 (P = 0.071);Gain of phosphorylation at T222 (P = 0.071);
MVP		0.98
MPC		2.3
ClinPred		0.99	D
GERP RS		6.1
Varity_R		0.99
gMVP		0.98

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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-18606175;