rs587783114

chrX-18604374-ACCAAGG-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 2P and 12B. PM4 BP6_Very_Strong BS2

The NM_001323289.2(CDKL5):c.1455_1460del(p.Ala486_Lys487del) variant causes a inframe deletion change. The variant allele was found at a frequency of 0.0000919 in 1,207,561 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 43 hemizygotes in GnomAD. Variant has been reported in ClinVar as Benign (★★★). Synonymous variant affecting the same amino acid position (i.e. T484T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000027 (0 hom., 2 hem., cov: 22)
  • Exomes 𝑓: 0.000098 (0 hom. 41 hem.)
• Consequence: CDKL5 NM_001323289.2 inframe_deletion
• Clinical Significance: Benign reviewed by expert panel U:1 B:4
• 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 -10 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_001323289.2.
• BP6: Variant X-18604374-ACCAAGG-A is Benign according to our data. Variant chrX-18604374-ACCAAGG-A is described in ClinVar as [Benign]. Clinvar id is 156642.Status of the report is reviewed_by_expert_panel, 3 stars.
• BS2: High Hemizygotes in GnomAd at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDKL5	NM_001323289.2	c.1455_1460del	p.Ala486_Lys487del	inframe_deletion	12/18	ENST00000623535.2
CDKL5	NM_001037343.2	c.1455_1460del	p.Ala486_Lys487del	inframe_deletion	13/22
CDKL5	NM_003159.3	c.1455_1460del	p.Ala486_Lys487del	inframe_deletion	12/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDKL5	ENST00000623535.2	c.1455_1460del	p.Ala486_Lys487del	inframe_deletion	12/18	1	NM_001323289.2	P1

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:4

Revision: reviewed by expert panel

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jun 19, 2016

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

Likely benign, no assertion criteria provided

curation

RettBASE

May 09, 2014

Found in unaffected female -

CDKL5 disorder Benign:1

Benign, reviewed by expert panel

curation

ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel

Feb 18, 2022

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). -

CDKL5-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 09, 2022

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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Oct 29, 2022

- -

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;