rs587783114

Variant names:

• chrX-18604374-ACCAAGG-A
• rs587783114
• NM_001323289.2:c.1455_1460delGGCCAA

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BS2_Supporting BA1

This summary comes from the ClinGen Evidence Repository: The allele frequency of the p.Ala486_Lys487del variant in CDKL5 is 0.03% in Latino/Admixed American sub population in gnomAD, which is high enough to be classified as benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BA1). The p.Ala486_Lys487del variant is observed in 1 unaffected individual (RettBASE, PMID 22867051) (BS2_supporting). In summary, the p.Ala486_Lys487del variant in CDKL5 is classified as benign based on the ACMG/AMP criteria applied (BA1, BS2_supporting). LINK:https://erepo.genome.network/evrepo/ui/classification/CA199357/MONDO:0100039/016

• Frequency:
  • Genomes: 𝑓 0.000027 (0 hom., 2 hem., cov: 22)
  • Exomes 𝑓: 0.000098 (0 hom. 41 hem.)
• Consequence: CDKL5 NM_001323289.2 disruptive_inframe_deletion
• Clinical Significance: Benign reviewed by expert panel U:1 B:5
• Conservation: PhyloP100: 6.36

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 Benign. Variant got -9 ACMG points.

• BS2: For more information check the summary or visit ClinGen Evidence Repository.
• BA1: 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.1455_1460delGGCCAA	p.Ala486_Lys487del	disruptive_inframe_deletion	Exon 12 of 18	ENST00000623535.2	NP_001310218.1
CDKL5	NM_001037343.2	c.1455_1460delGGCCAA	p.Ala486_Lys487del	disruptive_inframe_deletion	Exon 13 of 22		NP_001032420.1
CDKL5	NM_003159.3	c.1455_1460delGGCCAA	p.Ala486_Lys487del	disruptive_inframe_deletion	Exon 12 of 21		NP_003150.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDKL5	ENST00000623535.2	c.1455_1460delGGCCAA	p.Ala486_Lys487del	disruptive_inframe_deletion	Exon 12 of 18	1	NM_001323289.2	ENSP00000485244.1

Frequencies

GnomAD3 genomes AF: 0.0000270 AC: 3 AN: 111061 Hom.: 0 Cov.: 22 AF XY: 0.0000601 AC XY: 2 AN XY: 33303

Gnomad AFR AF: 0.0000328

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000378

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000660 AC: 12 AN: 181925 Hom.: 0 AF XY: 0.0000600 AC XY: 4 AN XY: 66647

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000329

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000247

Gnomad OTH exome AF: 0.000223

GnomAD4 exome AF: 0.0000985 AC: 108 AN: 1096500 Hom.: 0 AF XY: 0.000113 AC XY: 41 AN XY: 362182

Gnomad4 AFR exome AF: 0.0000380

Gnomad4 AMR exome AF: 0.000256

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: 0.000114

Gnomad4 OTH exome AF: 0.0000435

GnomAD4 genome AF: 0.0000270 AC: 3 AN: 111061 Hom.: 0 Cov.: 22 AF XY: 0.0000601 AC XY: 2 AN XY: 33303

Gnomad4 AFR AF: 0.0000328

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000378

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000529

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:5

Revision: reviewed by expert panel

Submissions by phenotype

CDKL5 disorder Benign:2

Feb 18, 2022

ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel

Significance: Benign

Review Status: reviewed by expert panel

Collection Method: curation

The allele frequency of the p.Ala486_Lys487del variant in CDKL5 is 0.03% in Latino/Admixed American sub population in gnomAD, which is high enough to be classified as benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BA1). The p.Ala486_Lys487del variant is observed in 1 unaffected individual (RettBASE, PMID 22867051) (BS2_supporting). In summary, the p.Ala486_Lys487del variant in CDKL5 is classified as benign based on the ACMG/AMP criteria applied (BA1, BS2_supporting). -

Sep 13, 2024

Centre for Population Genomics, CPG

Significance: Benign

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 benign. At least the following criteria are met: The allele frequency of this variant in at least one population in gnomAD is higher than the 0.03% threshold defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like Disorders VCEP 3.0 (BA1). -

not provided Uncertain:1

Jun 19, 2016

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1455_1460delGGCCAA variant in the CDKL5 gene has been previously identified in a female patient with developmental delay, absent speech, seizures, and difficulty walking; however, it was classified by the authors as a variant of unknown significance because it was inherited from her unaffected mother and both the patient and her mother had normal X-inactivation studies (Maortua et al., 2012). The variant results in an in-frame deletion of two amino acids. Therefore, based on the currently available information, it is unclear whether c.1455_1460delGGCCAA is a pathogenic variant or a rare benign variant. -

not specified Benign:1

May 09, 2014

RettBASE

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: curation

Found in unaffected female -

CDKL5-related disorder Benign:1

Aug 09, 2022

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs587783114; hg19: chrX-18622494;