X-18564526-GATATATATATATAT-GAT

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+5_145+16delATATATATATAT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000142 in 606,297 control chromosomes in the GnomAD database, including 3 homozygotes. There are 30 hemizygotes in GnomAD. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.000032 ( 0 hom., 2 hem., cov: 19)

Exomes 𝑓: 0.00016 ( 3 hom. 28 hem. )

Consequence

CDKL5
ENST00000623535.2 splice_region, intron

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 1.26

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-GATATATATATAT-G is Benign according to our data. Variant chrX-18564526-GATATATATATAT-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 1292563.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.000162 (83/513034) while in subpopulation NFE AF = 0.000164 (59/359623). AF 95% confidence interval is 0.00013. There are 3 homozygotes in GnomAdExome4. There are 28 alleles in the male GnomAdExome4 subpopulation. This position passed quality control check.

BS2

High AC in GnomAdExome4 at 83 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+17_145+28delATATATATATAT	intron	N/A	NP_001310218.1	O76039-2
CDKL5	NM_001037343.2		c.145+17_145+28delATATATATATAT	intron	N/A	NP_001032420.1	O76039-1
CDKL5	NM_003159.3		c.145+17_145+28delATATATATATAT	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+16delATATATATATAT	splice_region intron	N/A	ENSP00000485244.1	O76039-2
CDKL5	ENST00000379989.6	TSL:1	c.145+5_145+16delATATATATATAT	splice_region intron	N/A	ENSP00000369325.3	O76039-1
CDKL5	ENST00000379996.7	TSL:1	c.145+5_145+16delATATATATATAT	splice_region intron	N/A	ENSP00000369332.3	O76039-1

Frequencies

GnomAD3 genomes

AF:

0.0000322

AC:

AN:

93263

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000647

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000344

AC:

AN:

72668

AF XY:

0.00111

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000977

Gnomad NFE exome

AF:

0.000610

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000162

AC:

AN:

513034

Hom.:

AF XY:

0.000223

AC XY:

AN XY:

125428

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

13389

American (AMR)

AF:

0.00

AC:

AN:

24992

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

12214

East Asian (EAS)

AF:

0.00

AC:

AN:

19269

South Asian (SAS)

AF:

0.00

AC:

AN:

29143

European-Finnish (FIN)

AF:

0.000452

AC:

AN:

28779

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2004

European-Non Finnish (NFE)

AF:

0.000164

AC:

AN:

359623

Other (OTH)

AF:

0.000466

AC:

AN:

23621

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.726

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome 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

GnomAD4 genome

AF:

0.0000322

AC:

AN:

93263

Hom.:

Cov.:

AF XY:

0.0000855

AC XY:

AN XY:

23405

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

25686

American (AMR)

AF:

0.00

AC:

AN:

8314

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2323

East Asian (EAS)

AF:

0.00

AC:

AN:

2968

South Asian (SAS)

AF:

0.00

AC:

AN:

2063

European-Finnish (FIN)

AF:

0.00

AC:

AN:

3507

Middle Eastern (MID)

AF:

0.00

AC:

AN:

201

European-Non Finnish (NFE)

AF:

0.0000647

AC:

AN:

46394

Other (OTH)

AF:

0.00

AC:

AN:

1212

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

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:

0.00

Hom.:

ClinVar

ClinVar submissions

Significance:Benign/Likely 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)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.3

Mutation Taster

=100/0

polymorphism

(source)

Splicing

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over