rs75057928

Positions:

Variant summary

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

The NM_001323289.2(CDKL5):c.555-19C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0132 in 1,194,188 control chromosomes in the GnomAD database, including 585 homozygotes. There are 5,382 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.027 ( 93 hom., 925 hem., cov: 23)

Exomes 𝑓: 0.012 ( 492 hom. 4457 hem. )

Consequence

CDKL5
NM_001323289.2 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10O:1

Conservation

PhyloP100: 0.0660

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:

CDKL5 (HGNC:):

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-18587935-C-G is Benign according to our data. Variant chrX-18587935-C-G is described in ClinVar as [Benign]. Clinvar id is 94114.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-18587935-C-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.173 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE	Protein	UniProt
CDKL5	NM_001323289.2 linkuse as main transcript	c.555-19C>G	intron_variant	ENST00000623535.2	NP_001310218.1	O76039-2
CDKL5	NM_001037343.2 linkuse as main transcript	c.555-19C>G	intron_variant		NP_001032420.1	O76039-1
CDKL5	NM_003159.3 linkuse as main transcript	c.555-19C>G	intron_variant		NP_003150.1	O76039-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDKL5	ENST00000623535.2 linkuse as main transcript	c.555-19C>G		intron_variant		1	NM_001323289.2	ENSP00000485244.1		O76039-2

Frequencies

GnomAD3 genomes

AF:

0.0268

AC:

2994

AN:

111806

Hom.:

Cov.:

AF XY:

0.0270

AC XY:

918

AN XY:

34006

show subpopulations

Gnomad AFR

AF:

0.0621

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0184

Gnomad ASJ

AF:

0.000378

Gnomad EAS

AF:

0.184

Gnomad SAS

AF:

0.0650

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00851

Gnomad NFE

AF:

0.000432

Gnomad OTH

AF:

0.0252

GnomAD3 exomes

AF:

0.0328

AC:

5997

AN:

182878

Hom.:

248

AF XY:

0.0299

AC XY:

2024

AN XY:

67580

show subpopulations

Gnomad AFR exome

AF:

0.0686

Gnomad AMR exome

AF:

0.0463

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.195

Gnomad SAS exome

AF:

0.0514

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000588

Gnomad OTH exome

AF:

0.0229

GnomAD4 exome

AF:

0.0118

AC:

12741

AN:

1082328

Hom.:

492

Cov.:

AF XY:

0.0127

AC XY:

4457

AN XY:

349614

show subpopulations

Gnomad4 AFR exome

AF:

0.0700

Gnomad4 AMR exome

AF:

0.0429

Gnomad4 ASJ exome

AF:

0.0000519

Gnomad4 EAS exome

AF:

0.183

Gnomad4 SAS exome

AF:

0.0449

Gnomad4 FIN exome

AF:

0.0000247

Gnomad4 NFE exome

AF:

0.000472

Gnomad4 OTH exome

AF:

0.0234

GnomAD4 genome

AF:

0.0269

AC:

3007

AN:

111860

Hom.:

Cov.:

AF XY:

0.0272

AC XY:

925

AN XY:

34070

show subpopulations

Gnomad4 AFR

AF:

0.0624

Gnomad4 AMR

AF:

0.0183

Gnomad4 ASJ

AF:

0.000378

Gnomad4 EAS

AF:

0.184

Gnomad4 SAS

AF:

0.0641

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000432

Gnomad4 OTH

AF:

0.0262

Alfa

AF:

0.0151

Hom.:

Bravo

AF:

0.0328

ClinVar

Significance: Benign

Submissions summary: Benign:10Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 04, 2012	- -
Benign, no assertion criteria provided	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Feb 13, 2015	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	curation	RettBASE	May 09, 2014	Found in unaffected family members, likely to be rare polymorphism; shown in Nemos et al 2009 to have no effect on splicing -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	- -

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	Mar 03, 2015	- -

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). -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

6.7

DANN

Benign

0.51

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