rs122460157

Variant names:

• chrX-18581942-G-A
• rs122460157
• NM_001323289.2:c.455G>A

Your query was ambiguous. Multiple possible variants found:

• chrX-18581942-G-A
• chrX-18581942-G-T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_001323289.2(CDKL5):​c.455G>A​(p.Cys152Tyr) 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. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C152R) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 23)
• Consequence: CDKL5 NM_001323289.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 10.0
• Publications: 7 publications found

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]

CDKL5 Gene-Disease associations (from GenCC):

• CDKL5 disorder

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
• developmental and epileptic encephalopathy, 2

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• atypical Rett syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• genetic developmental and epileptic encephalopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• infantile spasms

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• precocious puberty

  Inheritance: XL Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 6 uncertain in NM_001323289.2
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-18581941-T-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 658951.Status of the report is reviewed_by_expert_panel, 3 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.979
• PP5: Variant X-18581942-G-A is Pathogenic according to our data. Variant chrX-18581942-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 495236.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDKL5	NM_001323289.2	c.455G>A	p.Cys152Tyr	missense_variant	Exon 7 of 18	ENST00000623535.2	NP_001310218.1
CDKL5	NM_001037343.2	c.455G>A	p.Cys152Tyr	missense_variant	Exon 8 of 22		NP_001032420.1
CDKL5	NM_003159.3	c.455G>A	p.Cys152Tyr	missense_variant	Exon 7 of 21		NP_003150.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDKL5	ENST00000623535.2	c.455G>A	p.Cys152Tyr	missense_variant	Exon 7 of 18	1	NM_001323289.2	ENSP00000485244.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 25

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Developmental and epileptic encephalopathy, 2 Pathogenic:1

Jan 01, 2018

NeuroMeGen, Hospital Clinico Santiago de Compostela

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Sep 20, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 495236). This missense change has been observed in individual(s) with clinical features of CDKL5-related conditions (PMID: 31780880). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 152 of the CDKL5 protein (p.Cys152Tyr). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.22	T;T;.;T;.;.
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	.;D;D;D;D;D
M_CAP	Pathogenic	0.88	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D
MetaSVM	Benign	-0.58	T
MutationAssessor	Pathogenic	3.2	M;.;.;M;.;M
PhyloP100		10
PrimateAI	Pathogenic	0.96	D
PROVEAN	Pathogenic	-10	D;.;.;D;.;.
REVEL	Pathogenic	0.69
Sift	Pathogenic	0.0	D;.;.;D;.;.
Sift4G	Pathogenic	0.0	D;.;.;D;D;D
Polyphen		1.0	D;.;.;D;.;.
Vest4		0.94
MutPred		0.87		Loss of stability (P = 0.079);Loss of stability (P = 0.079);Loss of stability (P = 0.079);Loss of stability (P = 0.079);Loss of stability (P = 0.079);Loss of stability (P = 0.079);
MVP		0.97
MPC		3.4
ClinPred		1.0	D
GERP RS		6.1
Varity_R		0.99
gMVP		0.99
Mutation Taster		=2/98	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs122460157; hg19: chrX-18600062;