X-18564526-GATATATATATATAT-GATATATATATATATAT

Variant names:

Variant summary

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

The ENST00000623535.2(CDKL5):c.145+4_145+5insAT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★★). The gene CDKL5 is included in the ClinGen Criteria Specification Registry.

Frequency

Genomes: 𝑓 0.012 ( 4 hom., 177 hem., cov: 19)

Exomes 𝑓: 0.061 ( 0 hom. 55 hem. )

Consequence

CDKL5
ENST00000623535.2 splice_region, intron

Scores

Not classified

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

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: G2P, Orphanet, 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

new If you want to explore the variant's impact on the transcript ENST00000623535.2, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Specifications for CDKL5 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP6

Variant X-18564526-G-GAT is Benign according to our data. Variant chrX-18564526-G-GAT is described in ClinVar as Benign. ClinVar VariationId is 414804.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0122 (1138/92992) while in subpopulation SAS AF = 0.0206 (42/2034). AF 95% confidence interval is 0.0157. There are 4 homozygotes in GnomAd4. There are 177 alleles in the male GnomAd4 subpopulation. Median coverage is 19. This position passed quality control check.

BS2

High AC in GnomAd4 at 1138 XL,AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000623535.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
CDKL5	NM_001323289.2	MANE Select	c.145+27_145+28dupAT	intron	N/A	NP_001310218.1	O76039-2
CDKL5	NM_001037343.2		c.145+27_145+28dupAT	intron	N/A	NP_001032420.1	O76039-1
CDKL5	NM_003159.3		c.145+27_145+28dupAT	intron	N/A	NP_003150.1	O76039-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
CDKL5	ENST00000623535.2	TSL:1 MANE Select	c.145+4_145+5insAT	splice_region intron	N/A	ENSP00000485244.1	O76039-2
CDKL5	ENST00000379989.6	TSL:1	c.145+4_145+5insAT	splice_region intron	N/A	ENSP00000369325.3	O76039-1
CDKL5	ENST00000379996.7	TSL:1	c.145+4_145+5insAT	splice_region intron	N/A	ENSP00000369332.3	O76039-1

Frequencies

GnomAD3 genomes

AF:

0.0123

AC:

1140

AN:

93017

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0146

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0159

Gnomad ASJ

AF:

0.00388

Gnomad EAS

AF:

0.0159

Gnomad SAS

AF:

0.0204

Gnomad FIN

AF:

0.00949

Gnomad MID

AF:

0.00498

Gnomad NFE

AF:

0.0103

Gnomad OTH

AF:

0.0190

GnomAD2 exomes

AF:

0.0517

AC:

3755

AN:

72668

AF XY:

0.000463

show subpopulations

Gnomad AFR exome

AF:

0.0103

Gnomad AMR exome

AF:

0.0266

Gnomad ASJ exome

AF:

0.0937

Gnomad EAS exome

AF:

0.0224

Gnomad FIN exome

AF:

0.118

Gnomad NFE exome

AF:

0.0519

Gnomad OTH exome

AF:

0.0453

GnomAD4 exome

AF:

0.0609

AC:

28132

AN:

461766

Hom.:

Cov.:

AF XY:

0.000591

AC XY:

AN XY:

93086

show subpopulations

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

African (AFR)

AF:

0.0545

AC:

675

AN:

12374

American (AMR)

AF:

0.0311

AC:

736

AN:

23695

Ashkenazi Jewish (ASJ)

AF:

0.0637

AC:

685

AN:

10760

East Asian (EAS)

AF:

0.0627

AC:

1091

AN:

17399

South Asian (SAS)

AF:

0.0346

AC:

892

AN:

25756

European-Finnish (FIN)

AF:

0.0655

AC:

1617

AN:

24704

Middle Eastern (MID)

AF:

0.0540

AC:

AN:

1832

European-Non Finnish (NFE)

AF:

0.0649

AC:

21009

AN:

323769

Other (OTH)

AF:

0.0618

AC:

1328

AN:

21477

⚠️ 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: 0.299

Heterozygous variant carriers

2210

4420

6629

8839

11049

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

664

1328

1992

2656

3320

<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:

0.0122

AC:

1138

AN:

92992

Hom.:

Cov.:

AF XY:

0.00759

AC XY:

177

AN XY:

23320

show subpopulations

African (AFR)

AF:

0.0146

AC:

374

AN:

25671

American (AMR)

AF:

0.0158

AC:

131

AN:

8285

Ashkenazi Jewish (ASJ)

AF:

0.00388

AC:

AN:

2321

East Asian (EAS)

AF:

0.0159

AC:

AN:

2947

South Asian (SAS)

AF:

0.0206

AC:

AN:

2034

European-Finnish (FIN)

AF:

0.00949

AC:

AN:

3479

Middle Eastern (MID)

AF:

0.00556

AC:

AN:

180

European-Non Finnish (NFE)

AF:

0.0103

AC:

478

AN:

46262

Other (OTH)

AF:

0.0189

AC:

AN:

1218

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

141

188

235

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.0360

Hom.:

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Developmental and epileptic encephalopathy, 2;CN128785:Angelman syndrome-like (1)

not provided (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.41

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over