X-18587977-A-G

Variant names:

• chrX-18587977-A-G
• rs267608500
• NM_001323289.2:c.578A>G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PP3 PP4 PP1 PM6_Strong PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The p.Asp193Gly variant in CDKL5 has been reported in at least 2 de novo occurrences (biological parentage unconfirmed) in affected individuals (PMID 23583054) (PM6_Strong). The p.Asp193Gly variant in CDKL5 is absent from gnomAD (PM2_Supporting). The variant has been reported to segregate in two informative meioses (PMID:23583054) (PP1). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). The p.Asp193Gly variant in CDKL5 has been reported in an individual with a clinical phenotype suggestive of a CDKL5-associated disorder (PP4). In summary, the p.Asp193Gly variant in CDKL5 is classified as likely pathogenic for CDKL5-associated disorder based on the ACMG/AMP criteria (PM6_strong, PM2_supporting, PP1, PP3, PP4). LINK:https://erepo.genome.network/evrepo/ui/classification/CA171648/MONDO:0100039/016

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.1e-7 (0 hom. 1 hem.)
• Consequence: CDKL5 NM_001323289.2 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:5
• Conservation: PhyloP100: 8.95

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 8 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM6: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDKL5	NM_001323289.2	c.578A>G	p.Asp193Gly	missense_variant	Exon 9 of 18	ENST00000623535.2	NP_001310218.1
CDKL5	NM_001037343.2	c.578A>G	p.Asp193Gly	missense_variant	Exon 10 of 22		NP_001032420.1
CDKL5	NM_003159.3	c.578A>G	p.Asp193Gly	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.578A>G	p.Asp193Gly	missense_variant	Exon 9 of 18	1	NM_001323289.2	ENSP00000485244.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 9.11e-7 AC: 1 AN: 1097378 Hom.: 0 Cov.: 29 AF XY: 0.00000276 AC XY: 1 AN XY: 362786

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: 0.00000119

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:5

Revision: reviewed by expert panel

Submissions by phenotype

Developmental and epileptic encephalopathy, 2 Pathogenic:2

Mar 13, 2014

RettBASE

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: curation

Mutation also found in affected half-siblings, likely maternal germline mosaicism; mutation not seen in asymptomatic mother; highly conserved amino acid, in catalytic domain; In silico prediction: SIFT = deleterious, MutationTaster = disease-causing, PolyPhen2 = probably damaging, AlignGVGD = pathogenic (C65) -

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

CDKL5 disorder Pathogenic:2

Mar 26, 2021

ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The p.Asp193Gly variant in CDKL5 has been reported in at least 2 de novo occurrences (biological parentage unconfirmed) in affected individuals (PMID 23583054) (PM6_Strong). The p.Asp193Gly variant in CDKL5 is absent from gnomAD (PM2_Supporting). The variant has been reported to segregate in two informative meioses (PMID: 23583054) (PP1). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). The p.Asp193Gly variant in CDKL5 has been reported in an individual with a clinical phenotype suggestive of a CDKL5-associated disorder (PP4). In summary, the p.Asp193Gly variant in CDKL5 is classified as likely pathogenic for CDKL5-associated disorder based on the ACMG/AMP criteria (PM6_strong, PM2_supporting, PP1, PP3, PP4). -

Jul 11, 2024

Centre for Population Genomics, CPG

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

This variant has been collected from RettBASE and curated to current modified ACMG/AMP criteria. Based on the classification scheme defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like Disorders Specifications to the ACMG/AMP Variant Interpretation Guidelines VCEP 3.0, this variant is classified as likely pathogenic. At least the following criteria are met: Another missense variant in the same codon has been classified as pathogenic (PM5) Variation ID: 1432338, PMID: 29655203 PMID: 27781031 Co-segregation with disease in multiple affected family members in at least 2 informative meiosis (PP1). 23583054 Computational prediction analysis tools suggests a deleterious impact (REVEL score>= 0.75) (PP3). At least one individual with this variant has been reported with a clinical phenotype consistent with CDKL5- related condition (PP4). PMID 23583054 This variant is absent from gnomAD v2/v3 (PM2_Supporting). Has been observed in at least 2 individuals with phenotypes consistent with CDKL5 disorder (PS4_Supporting). -

not provided Pathogenic:1

Jul 01, 2018

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.35	T;T;.;T;.;.
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	.;D;D;D;D;D
M_CAP	Pathogenic	0.95	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D
MetaSVM	Pathogenic	0.90	D
MutationAssessor	Pathogenic	4.1	H;.;.;H;.;H
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-7.0	D;.;.;D;.;.
REVEL	Pathogenic	0.82
Sift	Uncertain	0.0010	D;.;.;D;.;.
Sift4G	Uncertain	0.0030	D;.;.;D;D;D
Polyphen		1.0	D;.;.;D;.;.
Vest4		0.99
MutPred		0.96		Loss of stability (P = 0.0566);Loss of stability (P = 0.0566);Loss of stability (P = 0.0566);Loss of stability (P = 0.0566);Loss of stability (P = 0.0566);Loss of stability (P = 0.0566);
MVP		0.99
MPC		2.9
ClinPred		1.0	D
GERP RS		6.2
Varity_R		0.99
gMVP		1.0

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: rs267608500; hg19: chrX-18606097;