X-18564526-GATATATATATATAT-GATATATATATAT

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2

The NM_001323289.2(CDKL5):c.145+27_145+28delAT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0538 in 556,775 control chromosomes in the GnomAD database, including 12 homozygotes. There are 400 hemizygotes in GnomAD. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.010 ( 5 hom., 203 hem., cov: 19)

Exomes 𝑓: 0.063 ( 7 hom. 197 hem. )

Consequence

CDKL5
NM_001323289.2 intron

Scores

Not classified

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.405

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 -16 ACMG points.

BP6

Variant X-18564526-GAT-G is Benign according to our data. Variant chrX-18564526-GAT-G is described in ClinVar as Benign. ClinVar VariationId is 239511.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0105 (977/93077) while in subpopulation NFE AF = 0.015 (696/46299). AF 95% confidence interval is 0.0141. There are 5 homozygotes in GnomAd4. There are 203 alleles in the male GnomAd4 subpopulation. Median coverage is 19. This position passed quality control check.

BS2

High AC in GnomAd4 at 977 XL,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
CDKL5	NM_001323289.2 link	c.145+27_145+28delAT	intron_variant	Intron 4 of 17	ENST00000623535.2	NP_001310218.1	O76039-2
CDKL5	NM_001037343.2 link	c.145+27_145+28delAT	intron_variant	Intron 5 of 21		NP_001032420.1	O76039-1
CDKL5	NM_003159.3 link	c.145+27_145+28delAT	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+5_145+6delAT		splice_region_variant, intron_variant	Intron 4 of 17	1	NM_001323289.2	ENSP00000485244.1		O76039-2

Frequencies

GnomAD3 genomes

AF:

0.0105

AC:

977

AN:

93107

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00331

Gnomad AMI

AF:

0.0253

Gnomad AMR

AF:

0.00602

Gnomad ASJ

AF:

0.00431

Gnomad EAS

AF:

0.000337

Gnomad SAS

AF:

0.000485

Gnomad FIN

AF:

0.0302

Gnomad MID

AF:

0.0149

Gnomad NFE

AF:

0.0150

Gnomad OTH

AF:

0.00911

GnomAD2 exomes

AF:

0.0643

AC:

4674

AN:

72668

AF XY:

0.000648

show subpopulations

Gnomad AFR exome

AF:

0.0303

Gnomad AMR exome

AF:

0.0271

Gnomad ASJ exome

AF:

0.0691

Gnomad EAS exome

AF:

0.0222

Gnomad FIN exome

AF:

0.193

Gnomad NFE exome

AF:

0.0709

Gnomad OTH exome

AF:

0.0554

GnomAD4 exome

AF:

0.0625

AC:

29001

AN:

463698

Hom.:

AF XY:

0.00206

AC XY:

197

AN XY:

95852

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0544

AC:

680

AN:

12507

American (AMR)

AF:

0.0362

AC:

860

AN:

23733

Ashkenazi Jewish (ASJ)

AF:

0.0658

AC:

718

AN:

10911

East Asian (EAS)

AF:

0.0855

AC:

1459

AN:

17068

South Asian (SAS)

AF:

0.0255

AC:

675

AN:

26443

European-Finnish (FIN)

AF:

0.0979

AC:

2323

AN:

23731

Middle Eastern (MID)

AF:

0.0677

AC:

122

AN:

1802

European-Non Finnish (NFE)

AF:

0.0635

AC:

20724

AN:

326182

Other (OTH)

AF:

0.0675

AC:

1440

AN:

21321

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.311

Heterozygous variant carriers

2071

4142

6213

8284

10355

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

574

1148

1722

2296

2870

<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:

0.0105

AC:

977

AN:

93077

Hom.:

Cov.:

AF XY:

0.00870

AC XY:

203

AN XY:

23337

show subpopulations

African (AFR)

AF:

0.00331

AC:

AN:

25690

American (AMR)

AF:

0.00602

AC:

AN:

8309

Ashkenazi Jewish (ASJ)

AF:

0.00431

AC:

AN:

2321

East Asian (EAS)

AF:

0.000339

AC:

AN:

2949

South Asian (SAS)

AF:

0.000490

AC:

AN:

2040

European-Finnish (FIN)

AF:

0.0302

AC:

105

AN:

3479

Middle Eastern (MID)

AF:

0.0167

AC:

AN:

180

European-Non Finnish (NFE)

AF:

0.0150

AC:

696

AN:

46299

Other (OTH)

AF:

0.00904

AC:

AN:

1217

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

126

158

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:

0.0317

Hom.:

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:1

Aug 13, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.41

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