rs147819758

Variant names:

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBA1

The NM_001323289.2(CDKL5):c.2046+79G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00937 in 672,225 control chromosomes in the GnomAD database, including 93 homozygotes. There are 1,789 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.021 ( 50 hom., 657 hem., cov: 22)

Exomes 𝑓: 0.0069 ( 43 hom. 1132 hem. )

Consequence

CDKL5
NM_001323289.2 intron

Scores

Clinical Significance

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

Conservation

PhyloP100: -3.65

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=-0.98).

BP6

Variant X-18608991-G-A is Benign according to our data. Variant chrX-18608991-G-A is described in ClinVar as Benign. ClinVar VariationId is 156076.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0593 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
CDKL5	NM_001323289.2 link	c.2046+79G>A	intron_variant	Intron 13 of 17	ENST00000623535.2	NP_001310218.1	O76039-2
CDKL5	NM_001037343.2 link	c.2046+79G>A	intron_variant	Intron 14 of 21		NP_001032420.1	O76039-1
CDKL5	NM_003159.3 link	c.2046+79G>A	intron_variant	Intron 13 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.2046+79G>A		intron_variant	Intron 13 of 17	1	NM_001323289.2	ENSP00000485244.1		O76039-2

Frequencies

GnomAD3 genomes

AF:

0.0215

AC:

2404

AN:

112034

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0616

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00934

Gnomad ASJ

AF:

0.0302

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00444

Gnomad FIN

AF:

0.00347

Gnomad MID

AF:

0.0504

Gnomad NFE

AF:

0.00483

Gnomad OTH

AF:

0.0192

GnomAD4 exome

AF:

0.00695

AC:

3891

AN:

560138

Hom.:

AF XY:

0.00683

AC XY:

1132

AN XY:

165712

show subpopulations

African (AFR)

AF:

0.0584

AC:

948

AN:

16227

American (AMR)

AF:

0.00703

AC:

210

AN:

29865

Ashkenazi Jewish (ASJ)

AF:

0.0283

AC:

437

AN:

15436

East Asian (EAS)

AF:

0.00

AC:

AN:

27014

South Asian (SAS)

AF:

0.00182

AC:

AN:

40617

European-Finnish (FIN)

AF:

0.00393

AC:

147

AN:

37395

Middle Eastern (MID)

AF:

0.0103

AC:

AN:

3100

European-Non Finnish (NFE)

AF:

0.00473

AC:

1712

AN:

362218

Other (OTH)

AF:

0.0117

AC:

331

AN:

28266

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

142

284

425

567

709

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

150

200

250

<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:

0.0215

AC:

2406

AN:

112087

Hom.:

Cov.:

AF XY:

0.0191

AC XY:

657

AN XY:

34309

show subpopulations

African (AFR)

AF:

0.0616

AC:

1898

AN:

30811

American (AMR)

AF:

0.00933

AC:

AN:

10615

Ashkenazi Jewish (ASJ)

AF:

0.0302

AC:

AN:

2646

East Asian (EAS)

AF:

0.00

AC:

AN:

3591

South Asian (SAS)

AF:

0.00445

AC:

AN:

2696

European-Finnish (FIN)

AF:

0.00347

AC:

AN:

6055

Middle Eastern (MID)

AF:

0.0553

AC:

AN:

217

European-Non Finnish (NFE)

AF:

0.00479

AC:

255

AN:

53246

Other (OTH)

AF:

0.0190

AC:

AN:

1526

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

175

262

350

437

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

140

<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:

0.0143

Hom.:

Bravo

AF:

0.0240

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:Benign

Review Status:no assertion criteria provided

Collection Method:curation

- -

CDKL5 disorder

Benign:1

Sep 16, 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). -

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

-0.98

CADD

Benign

0.0030

(source)

DANN

Benign

0.50

PhyloP100

-3.6

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

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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