Variant rs4825261 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001323289.2(CDKL5):c.283-99C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.314 in 781,995 control chromosomes in the GnomAD database, including 28,867 homozygotes. There are 71,175 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.28 ( 3433 hom., 9251 hem., cov: 23)

Exomes 𝑓: 0.32 ( 25434 hom. 61924 hem. )

Consequence

CDKL5
NM_001323289.2 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4O:1

Conservation

PhyloP100: -0.739

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.82).

BP6

Variant X-18579749-C-A is Benign according to our data. Variant chrX-18579749-C-A is described in ClinVar as [Benign]. Clinvar id is 156085.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.439 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE	Protein
CDKL5	NM_001323289.2 linkuse as main transcript	c.283-99C>A	intron_variant	ENST00000623535.2	NP_001310218.1
CDKL5	NM_001037343.2 linkuse as main transcript	c.283-99C>A	intron_variant		NP_001032420.1
CDKL5	NM_003159.3 linkuse as main transcript	c.283-99C>A	intron_variant		NP_003150.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDKL5	ENST00000623535.2 linkuse as main transcript	c.283-99C>A		intron_variant		1	NM_001323289.2	ENSP00000485244	P1	O76039-2

Frequencies

GnomAD3 genomes

AF:

0.283

AC:

31182

AN:

110051

Hom.:

3437

Cov.:

AF XY:

0.285

AC XY:

9237

AN XY:

32391

show subpopulations

Gnomad AFR

AF:

0.165

Gnomad AMI

AF:

0.266

Gnomad AMR

AF:

0.425

Gnomad ASJ

AF:

0.410

Gnomad EAS

AF:

0.459

Gnomad SAS

AF:

0.411

Gnomad FIN

AF:

0.260

Gnomad MID

AF:

0.285

Gnomad NFE

AF:

0.302

Gnomad OTH

AF:

0.283

GnomAD4 exome

AF:

0.319

AC:

214153

AN:

671895

Hom.:

25434

AF XY:

0.337

AC XY:

61924

AN XY:

183723

show subpopulations

Gnomad4 AFR exome

AF:

0.152

Gnomad4 AMR exome

AF:

0.523

Gnomad4 ASJ exome

AF:

0.392

Gnomad4 EAS exome

AF:

0.465

Gnomad4 SAS exome

AF:

0.413

Gnomad4 FIN exome

AF:

0.270

Gnomad4 NFE exome

AF:

0.298

Gnomad4 OTH exome

AF:

0.315

GnomAD4 genome

AF:

0.283

AC:

31182

AN:

110100

Hom.:

3433

Cov.:

AF XY:

0.285

AC XY:

9251

AN XY:

32450

show subpopulations

Gnomad4 AFR

AF:

0.165

Gnomad4 AMR

AF:

0.426

Gnomad4 ASJ

AF:

0.410

Gnomad4 EAS

AF:

0.458

Gnomad4 SAS

AF:

0.414

Gnomad4 FIN

AF:

0.260

Gnomad4 NFE

AF:

0.302

Gnomad4 OTH

AF:

0.283

Alfa

AF:

0.168

Hom.:

897

Bravo

AF:

0.298

ClinVar

Significance: Benign

Submissions summary: Benign:4Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2Other: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 SNP -

CDKL5 disorder

Benign:1

Benign, criteria provided, single submitter

curation

Centre for Population Genomics, CPG

Jul 12, 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 v4 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

-0.82

CADD

Benign

0.074

DANN

Benign

0.56

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over