X-18564526-GATATATATATATAT-GATATATATAT

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP6_Moderate

The ENST00000623535.2(CDKL5):c.145+5_145+8delATAT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0039 in 594,491 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.000043 ( 0 hom., 0 hem., cov: 19)

Exomes 𝑓: 0.0046 ( 0 hom. 0 hem. )

Consequence

CDKL5
ENST00000623535.2 splice_region, intron

Scores

Not classified

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.740

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: Likely_benign. The variant received -2 ACMG points.

BP6

Variant X-18564526-GATAT-G is Benign according to our data. Variant chrX-18564526-GATAT-G is described in ClinVar as Benign. ClinVar VariationId is 1168486.Status of the report is criteria_provided_single_submitter, 1 stars.

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+25_145+28delATAT	intron	N/A	NP_001310218.1	O76039-2
CDKL5	NM_001037343.2		c.145+25_145+28delATAT	intron	N/A	NP_001032420.1	O76039-1
CDKL5	NM_003159.3		c.145+25_145+28delATAT	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+5_145+8delATAT	splice_region intron	N/A	ENSP00000485244.1	O76039-2
CDKL5	ENST00000379989.6	TSL:1	c.145+5_145+8delATAT	splice_region intron	N/A	ENSP00000369325.3	O76039-1
CDKL5	ENST00000379996.7	TSL:1	c.145+5_145+8delATAT	splice_region intron	N/A	ENSP00000369332.3	O76039-1

Frequencies

GnomAD3 genomes

AF:

0.0000429

AC:

AN:

93248

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000120

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000285

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000431

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00334

AC:

243

AN:

72668

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00474

Gnomad AMR exome

AF:

0.00310

Gnomad ASJ exome

AF:

0.00180

Gnomad EAS exome

AF:

0.00212

Gnomad FIN exome

AF:

0.00472

Gnomad NFE exome

AF:

0.00340

Gnomad OTH exome

AF:

0.00254

GnomAD4 exome

AF:

0.00462

AC:

2317

AN:

501268

Hom.:

AF XY:

0.00

AC XY:

AN XY:

120376

show subpopulations

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

African (AFR)

AF:

0.00520

AC:

AN:

13068

American (AMR)

AF:

0.00345

AC:

AN:

24649

Ashkenazi Jewish (ASJ)

AF:

0.00564

AC:

AN:

11889

East Asian (EAS)

AF:

0.00800

AC:

149

AN:

18631

South Asian (SAS)

AF:

0.00206

AC:

AN:

28586

European-Finnish (FIN)

AF:

0.00465

AC:

129

AN:

27762

Middle Eastern (MID)

AF:

0.00667

AC:

AN:

1949

European-Non Finnish (NFE)

AF:

0.00456

AC:

1603

AN:

351735

Other (OTH)

AF:

0.00626

AC:

144

AN:

22999

⚠️ 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: 0.258

Heterozygous variant carriers

274

549

823

1098

1372

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

114

152

190

<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:

0.0000429

AC:

AN:

93223

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

23403

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

25711

American (AMR)

AF:

0.000120

AC:

AN:

8316

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2323

East Asian (EAS)

AF:

0.00

AC:

AN:

2953

South Asian (SAS)

AF:

0.00

AC:

AN:

2042

European-Finnish (FIN)

AF:

0.000285

AC:

AN:

3505

Middle Eastern (MID)

AF:

0.00

AC:

AN:

180

European-Non Finnish (NFE)

AF:

0.0000431

AC:

AN:

46376

Other (OTH)

AF:

0.00

AC:

AN:

1222

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.00215951), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.338

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.00265

Hom.:

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

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

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.74

Mutation Taster

=100/0

polymorphism

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over