rs267608448

Variant names:

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_001323289.2(CDKL5):c.283-43G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000707 in 1,161,061 control chromosomes in the GnomAD database, including 2 homozygotes. There are 261 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.00060 ( 0 hom., 17 hem., cov: 23)

Exomes 𝑓: 0.00072 ( 2 hom. 244 hem. )

Consequence

CDKL5
NM_001323289.2 intron

Scores

Clinical Significance

Benign criteria provided, single submitter B:2O:1

Conservation

PhyloP100: 0.868

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

CDKL5 disorder
Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
developmental and epileptic encephalopathy, 2
Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
atypical Rett syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
genetic developmental and epileptic encephalopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
infantile spasms
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
precocious puberty
Inheritance: XL Classification: LIMITED Submitted by: Ambry Genetics

CDKL5 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.8).

BP6

Variant X-18579805-G-A is Benign according to our data. Variant chrX-18579805-G-A is described in ClinVar as Benign. ClinVar VariationId is 156084.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000595 (66/110918) while in subpopulation NFE AF = 0.001 (53/52864). AF 95% confidence interval is 0.000787. There are 0 homozygotes in GnomAd4. There are 17 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.

BS2

High AC in GnomAd4 at 66 XL,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein
CDKL5	NM_001323289.2 link	c.283-43G>A	intron_variant	Intron 5 of 17	ENST00000623535.2	NP_001310218.1
CDKL5	NM_001037343.2 link	c.283-43G>A	intron_variant	Intron 6 of 21		NP_001032420.1
CDKL5	NM_003159.3 link	c.283-43G>A	intron_variant	Intron 5 of 20		NP_003150.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDKL5	ENST00000623535.2 link	c.283-43G>A		intron_variant	Intron 5 of 17	1	NM_001323289.2	ENSP00000485244.1

Frequencies

GnomAD3 genomes

AF:

0.000595

AC:

AN:

110875

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000229

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000193

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000281

Gnomad SAS

AF:

0.000757

Gnomad FIN

AF:

0.000172

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00100

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000594

AC:

108

AN:

181815

AF XY:

0.000642

show subpopulations

Gnomad AFR exome

AF:

0.000156

Gnomad AMR exome

AF:

0.0000735

Gnomad ASJ exome

AF:

0.000805

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000630

Gnomad NFE exome

AF:

0.000885

Gnomad OTH exome

AF:

0.000449

GnomAD4 exome

AF:

0.000719

AC:

755

AN:

1050143

Hom.:

Cov.:

AF XY:

0.000750

AC XY:

244

AN XY:

325411

show subpopulations

African (AFR)

AF:

0.000472

AC:

AN:

25434

American (AMR)

AF:

0.0000571

AC:

AN:

35043

Ashkenazi Jewish (ASJ)

AF:

0.000897

AC:

AN:

18951

East Asian (EAS)

AF:

0.00

AC:

AN:

29834

South Asian (SAS)

AF:

0.00104

AC:

AN:

52786

European-Finnish (FIN)

AF:

0.000223

AC:

AN:

40287

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4014

European-Non Finnish (NFE)

AF:

0.000799

AC:

639

AN:

799430

Other (OTH)

AF:

0.000473

AC:

AN:

44364

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.459

Heterozygous variant carriers

109

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

104

130

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000595

AC:

AN:

110918

Hom.:

Cov.:

AF XY:

0.000512

AC XY:

AN XY:

33218

show subpopulations

African (AFR)

AF:

0.000229

AC:

AN:

30624

American (AMR)

AF:

0.000192

AC:

AN:

10391

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2628

East Asian (EAS)

AF:

0.000282

AC:

AN:

3549

South Asian (SAS)

AF:

0.000760

AC:

AN:

2630

European-Finnish (FIN)

AF:

0.000172

AC:

AN:

5827

Middle Eastern (MID)

AF:

0.00

AC:

AN:

213

European-Non Finnish (NFE)

AF:

0.00100

AC:

AN:

52864

Other (OTH)

AF:

0.00

AC:

AN:

1509

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00105

Hom.:

Bravo

AF:

0.000548

ClinVar

Significance: Benign

Submissions summary: Benign:2Other:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Mar 13, 2014

RettBASE

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:curation

Unlikely to be pathogenic, not predicted to change splicing; however, there is no empirical evidence for this -

CDKL5 disorder

Benign:1

Jul 12, 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 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). -

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

-0.80

CADD

Benign

1.9

(source)

DANN

Benign

0.58

PhyloP100

0.87

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over