rs199814742

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001323289.2(CDKL5):c.145+17A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00558 in 623,579 control chromosomes in the GnomAD database, including 30 homozygotes. There are 1,116 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0036 ( 2 hom., 118 hem., cov: 21)

Exomes 𝑓: 0.0060 ( 28 hom. 998 hem. )

Consequence

CDKL5
NM_001323289.2 intron

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8O:1

Conservation

PhyloP100: -0.180

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=-0.91).

BP6

Variant X-18564539-A-G is Benign according to our data. Variant chrX-18564539-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 136709.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-18564539-A-G is described in Lovd as [Benign]. Variant chrX-18564539-A-G is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00357 (381/106814) while in subpopulation NFE AF= 0.00448 (233/52042). AF 95% confidence interval is 0.00401. There are 2 homozygotes in gnomad4. There are 118 alleles in male gnomad4 subpopulation. Median coverage is 21. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
CDKL5	NM_001323289.2 link	c.145+17A>G	intron_variant	Intron 4 of 17	ENST00000623535.2	NP_001310218.1	O76039-2
CDKL5	NM_001037343.2 link	c.145+17A>G	intron_variant	Intron 5 of 21		NP_001032420.1	O76039-1
CDKL5	NM_003159.3 link	c.145+17A>G	intron_variant	Intron 4 of 20		NP_003150.1	O76039-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDKL5	ENST00000623535.2 link	c.145+17A>G		intron_variant	Intron 4 of 17	1	NM_001323289.2	ENSP00000485244.1		O76039-2

Frequencies

GnomAD3 genomes

AF:

0.00359

AC:

383

AN:

106819

Hom.:

Cov.:

AF XY:

0.00397

AC XY:

119

AN XY:

29959

show subpopulations

Gnomad AFR

AF:

0.000339

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00133

Gnomad ASJ

AF:

0.0298

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00366

Gnomad FIN

AF:

0.00430

Gnomad MID

AF:

0.0429

Gnomad NFE

AF:

0.00451

Gnomad OTH

AF:

0.00561

GnomAD3 exomes

AF:

0.00980

AC:

645

AN:

65810

Hom.:

AF XY:

0.0124

AC XY:

228

AN XY:

18352

show subpopulations

Gnomad AFR exome

AF:

0.00364

Gnomad AMR exome

AF:

0.00570

Gnomad ASJ exome

AF:

0.0419

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00392

Gnomad FIN exome

AF:

0.00365

Gnomad NFE exome

AF:

0.0118

Gnomad OTH exome

AF:

0.0159

GnomAD4 exome

AF:

0.00600

AC:

3101

AN:

516765

Hom.:

Cov.:

AF XY:

0.00888

AC XY:

998

AN XY:

112335

show subpopulations

Gnomad4 AFR exome

AF:

0.00153

Gnomad4 AMR exome

AF:

0.00466

Gnomad4 ASJ exome

AF:

0.0387

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00407

Gnomad4 FIN exome

AF:

0.00534

Gnomad4 NFE exome

AF:

0.00556

Gnomad4 OTH exome

AF:

0.00725

GnomAD4 genome

AF:

0.00357

AC:

381

AN:

106814

Hom.:

Cov.:

AF XY:

0.00394

AC XY:

118

AN XY:

29966

show subpopulations

Gnomad4 AFR

AF:

0.000339

Gnomad4 AMR

AF:

0.00133

Gnomad4 ASJ

AF:

0.0298

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00369

Gnomad4 FIN

AF:

0.00430

Gnomad4 NFE

AF:

0.00448

Gnomad4 OTH

AF:

0.00555

Alfa

AF:

0.00695

Hom.:

Bravo

AF:

0.00322

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

May 09, 2014

RettBASE

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: curation

- -

Mar 15, 2012

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 29, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Developmental and epileptic encephalopathy, 2

Benign:2

May 03, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

CDKL5 disorder

Benign:1

Jul 04, 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). The computational splicing predictor SpliceAI does not support significant splicing alteration (score of <=0.1) (BP4). -

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

Benign:1

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Other:1

RettBASE

Significance: not provided

Review Status: flagged submission

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

0.77

DANN

Benign

0.54

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