Variant rs777490768 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got -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, splice_polypyrimidine_tract, intron

Scores

Splicing: ADA: 0.00005398

Clinical Significance

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

Conservation

PhyloP100: 0.351

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 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got -1 ACMG points.

BP4

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE
CDKL5	NM_001323289.2 linkuse as main transcript	c.65-4A>G	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant	ENST00000623535.2
CDKL5	NM_001037343.2 linkuse as main transcript	c.65-4A>G	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant
CDKL5	NM_003159.3 linkuse as main transcript	c.65-4A>G	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDKL5	ENST00000623535.2 linkuse as main transcript	c.65-4A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_001323289.2	P1	O76039-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000547

AC:

AN:

182920

Hom.:

AF XY:

0.00

AC XY:

AN XY:

67452

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 SAS 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

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000121

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000434

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2Benign:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Mar 14, 2016

- -

CDKL5 disorder

Uncertain:1

Uncertain significance, reviewed by expert panel

curation

ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel

Oct 13, 2023

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). -

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

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Mar 09, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.57

CADD

Benign

DANN

Benign

0.82

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over