rs3752484

Positions:

• chrX-18620084-T-A
• chrX-18620084-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001323289.2(CDKL5):​c.2376+118T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.404 in 492,998 control chromosomes in the GnomAD database, including 30,439 homozygotes. There are 64,539 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.45 (8739 hom., 14975 hem., cov: 23)
  • Exomes 𝑓: 0.39 (21700 hom. 49564 hem.)
• Consequence: CDKL5 NM_001323289.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4 O:1
• Conservation: PhyloP100: 0.251

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant X-18620084-T-A is Benign according to our data. Variant chrX-18620084-T-A is described in ClinVar as [Benign]. Clinvar id is 156079.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.656 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDKL5	NM_001323289.2	c.2376+118T>A		intron_variant		ENST00000623535.2	NP_001310218.1
CDKL5	NM_001037343.2	c.2376+118T>A		intron_variant			NP_001032420.1
CDKL5	NM_003159.3	c.2376+118T>A		intron_variant			NP_003150.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDKL5	ENST00000623535.2	c.2376+118T>A		intron_variant		1	NM_001323289.2	ENSP00000485244	P1

Frequencies

GnomAD3 genomes AF: 0.446 AC: 49610 AN: 111239 Hom.: 8735 Cov.: 23 AF XY: 0.446 AC XY: 14916 AN XY: 33433

Gnomad AFR AF: 0.626

Gnomad AMI AF: 0.266

Gnomad AMR AF: 0.631

Gnomad ASJ AF: 0.460

Gnomad EAS AF: 0.679

Gnomad SAS AF: 0.486

Gnomad FIN AF: 0.259

Gnomad MID AF: 0.386

Gnomad NFE AF: 0.311

Gnomad OTH AF: 0.462

GnomAD4 exome AF: 0.391 AC: 149359 AN: 381706 Hom.: 21700 AF XY: 0.407 AC XY: 49564 AN XY: 121764

Gnomad4 AFR exome AF: 0.641

Gnomad4 AMR exome AF: 0.736

Gnomad4 ASJ exome AF: 0.448

Gnomad4 EAS exome AF: 0.689

Gnomad4 SAS exome AF: 0.475

Gnomad4 FIN exome AF: 0.273

Gnomad4 NFE exome AF: 0.322

Gnomad4 OTH exome AF: 0.409

GnomAD4 genome AF: 0.446 AC: 49676 AN: 111292 Hom.: 8739 Cov.: 23 AF XY: 0.447 AC XY: 14975 AN XY: 33496

Gnomad4 AFR AF: 0.626

Gnomad4 AMR AF: 0.631

Gnomad4 ASJ AF: 0.460

Gnomad4 EAS AF: 0.679

Gnomad4 SAS AF: 0.489

Gnomad4 FIN AF: 0.259

Gnomad4 NFE AF: 0.311

Gnomad4 OTH AF: 0.460

Alfa AF: 0.371 Hom.: 2550

Bravo AF: 0.491

ClinVar

Significance: Benign

Submissions summary: Benign:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2 Other:1

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
not provided, flagged submission	literature only	RettBASE	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 14, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not specified Benign:1

Benign, no assertion criteria provided

curation

RettBASE

Mar 13, 2014

Common polymorphism in intron 16 -

CDKL5 disorder Benign:1

Benign, criteria provided, single submitter

curation

Centre for Population Genomics, CPG

Sep 16, 2024

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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.60
DANN	Benign	0.74

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: rs3752484; hg19: chrX-18638204;