Genetic Variant CDKL5:c.145+25_145+28dupATAT (chrX-18564526-G-GATAT) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_ModerateBS1BS2

The NM_001323289.2(CDKL5):c.145+25_145+28dupATAT variant causes a intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.00023 ( 0 hom., 1 hem., cov: 19)

Exomes 𝑓: 0.0013 ( 0 hom. 0 hem. )

Consequence

CDKL5
NM_001323289.2 intron

Scores

Not classified

Clinical Significance

Benign criteria provided, single submitter B:1

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 -10 ACMG points.

BP6

Variant X-18564526-G-GATAT is Benign according to our data. Variant chrX-18564526-G-GATAT is described in ClinVar as Benign. ClinVar VariationId is 1169508.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000225 (21/93223) while in subpopulation AMR AF = 0.000361 (3/8316). AF 95% confidence interval is 0.000182. There are 0 homozygotes in GnomAd4. There are 1 alleles in the male GnomAd4 subpopulation. Median coverage is 19. This position passed quality control check.

BS2

High AC in GnomAd4 at 21 XL,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein
CDKL5	NM_001323289.2 link	c.145+25_145+28dupATAT	intron_variant	Intron 4 of 17	ENST00000623535.2	NP_001310218.1
CDKL5	NM_001037343.2 link	c.145+25_145+28dupATAT	intron_variant	Intron 5 of 21		NP_001032420.1
CDKL5	NM_003159.3 link	c.145+25_145+28dupATAT	intron_variant	Intron 4 of 20		NP_003150.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDKL5	ENST00000623535.2 link	c.145+4_145+5insATAT		splice_region_variant, intron_variant	Intron 4 of 17	1	NM_001323289.2	ENSP00000485244.1

Frequencies

GnomAD3 genomes

AF:

0.000225

AC:

AN:

93248

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000350

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000361

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:

0.000172

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000798

AC:

AN:

72668

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.000175

Gnomad AMR exome

AF:

0.000543

Gnomad ASJ exome

AF:

0.000901

Gnomad EAS exome

AF:

0.000706

Gnomad FIN exome

AF:

0.00130

Gnomad NFE exome

AF:

0.000867

Gnomad OTH exome

AF:

0.000509

GnomAD4 exome

AF:

0.00125

AC:

637

AN:

509058

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

123528

show subpopulations

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

African (AFR)

AF:

0.000827

AC:

AN:

13307

American (AMR)

AF:

0.000925

AC:

AN:

24864

Ashkenazi Jewish (ASJ)

AF:

0.00149

AC:

AN:

12092

East Asian (EAS)

AF:

0.000994

AC:

AN:

19107

South Asian (SAS)

AF:

0.000658

AC:

AN:

28869

European-Finnish (FIN)

AF:

0.000879

AC:

AN:

28455

Middle Eastern (MID)

AF:

0.00151

AC:

AN:

1989

European-Non Finnish (NFE)

AF:

0.00136

AC:

485

AN:

356933

Other (OTH)

AF:

0.00145

AC:

AN:

23442

⚠️ 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: 0.260

Heterozygous variant carriers

152

228

304

380

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

GnomAD4 genome

AF:

0.000225

AC:

AN:

93223

Hom.:

Cov.:

AF XY:

0.0000427

AC XY:

AN XY:

23399

show subpopulations

African (AFR)

AF:

0.000350

AC:

AN:

25713

American (AMR)

AF:

0.000361

AC:

AN:

8316

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2321

East Asian (EAS)

AF:

0.00

AC:

AN:

2954

South Asian (SAS)

AF:

0.00

AC:

AN:

2042

European-Finnish (FIN)

AF:

0.000285

AC:

AN:

3504

Middle Eastern (MID)

AF:

0.00

AC:

AN:

180

European-Non Finnish (NFE)

AF:

0.000173

AC:

AN:

46376

Other (OTH)

AF:

0.00

AC:

AN:

1222

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

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:

0.00173

Hom.:

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

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

Benign:1

Jan 11, 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

(source)

Splicing

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

Publications

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X-18564526-GATATATATATATAT-GATATATATATATATATAT

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