Variant summary

Our verdict is Uncertain significance. The variant received -1 ACMG points: 0P and 1B. BP4

This summary comes from the ClinGen Evidence Repository: The c.65-4A>G variant in CDKL5 is present in 1 XX individual in gnomAD (does not meet BS1 based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions). Splice prediction analysis, using multiple computational tools does not suggest an impact to splicing (BP4). In summary, the c.65-4A>G in CDKL5 is classified as a variant of uncertain significance based on the ACMG/AMP criteria (BP4). LINK:https://erepo.genome.network/evrepo/ui/classification/CA10360187/MONDO:0100039/034

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 9.3e-7 ( 0 hom. 0 hem. )

Consequence

CDKL5
NM_001323289.2 splice_region, intron

Scores

Splicing: ADA: 0.00005398

Clinical Significance

Uncertain significance reviewed by expert panel U:2B:1

Conservation

PhyloP100: 0.351

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: Uncertain_significance. The variant received -1 ACMG points.

BP4

For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001323289.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
CDKL5	NM_001323289.2	MANE Select	c.65-4A>G	splice_region intron	N/A	NP_001310218.1
CDKL5	NM_001037343.2		c.65-4A>G	splice_region intron	N/A	NP_001032420.1
CDKL5	NM_003159.3		c.65-4A>G	splice_region intron	N/A	NP_003150.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
CDKL5	ENST00000623535.2	TSL:1 MANE Select	c.65-4A>G	splice_region intron	N/A	ENSP00000485244.1
CDKL5	ENST00000379989.6	TSL:1	c.65-4A>G	splice_region intron	N/A	ENSP00000369325.3
CDKL5	ENST00000379996.7	TSL:1	c.65-4A>G	splice_region intron	N/A	ENSP00000369332.3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000547

AC:

AN:

182920

AF XY:

0.00

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:

0.00

Gnomad NFE exome

AF:

0.0000122

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

9.28e-7

AC:

AN:

1077342

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

346350

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26028

American (AMR)

AF:

0.00

AC:

AN:

35165

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19225

East Asian (EAS)

AF:

0.00

AC:

AN:

30058

South Asian (SAS)

AF:

0.00

AC:

AN:

53648

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40241

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4081

European-Non Finnish (NFE)

AF:

0.00000121

AC:

AN:

823493

Other (OTH)

AF:

0.00

AC:

AN:

45403

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000434

Hom.:

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

CDKL5 disorder (1)

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

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.57

CADD

Benign

(source)

DANN

Benign

0.82

PhyloP100

0.35

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000054

dbscSNV1_RF

Benign

0.026

SpliceAI score (max)

0.010

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.

rs777490768

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over