rs191864898

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001323289.2(CDKL5):c.-391G>T variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00634 in 113,430 control chromosomes in the GnomAD database, including 7 homozygotes. There are 214 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0063 ( 7 hom., 213 hem., cov: 24)

Exomes 𝑓: 0.0075 ( 0 hom. 1 hem. )

Consequence

CDKL5
NM_001323289.2 upstream_gene

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.199

Publications

2 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.82).

BP6

Variant X-18425467-G-T is Benign according to our data. Variant chrX-18425467-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 158175.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00634 (718/113297) while in subpopulation NFE AF = 0.00997 (532/53351). AF 95% confidence interval is 0.00927. There are 7 homozygotes in GnomAd4. There are 213 alleles in the male GnomAd4 subpopulation. Median coverage is 24. This position passed quality control check.

BS2

High AC in GnomAd4 at 718 XL,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDKL5	NM_001323289.2 link	c.-391G>T		upstream_gene_variant		ENST00000623535.2	NP_001310218.1
CDKL5	NM_003159.3 link	c.-391G>T		upstream_gene_variant			NP_003150.1

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Protein
CDKL5	ENST00000623535.2 link	c.-391G>T	upstream_gene_variant	1	NM_001323289.2	ENSP00000485244.1
CDKL5	ENST00000379996.7 link	c.-391G>T	upstream_gene_variant	1		ENSP00000369332.3
CDKL5	ENST00000674046.1 link	c.-391G>T	upstream_gene_variant			ENSP00000501174.1

Frequencies

GnomAD3 genomes

AF:

0.00634

AC:

718

AN:

113248

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00131

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00600

Gnomad ASJ

AF:

0.00789

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000355

Gnomad FIN

AF:

0.00728

Gnomad MID

AF:

0.00418

Gnomad NFE

AF:

0.00997

Gnomad OTH

AF:

0.00716

GnomAD4 exome

AF:

0.00752

AC:

AN:

133

Hom.:

AF XY:

0.0133

AC XY:

AN XY:

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

American (AMR)

AF:

0.00

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AF:

0.00

AC:

AN:

South Asian (SAS)

AF:

0.00

AC:

AN:

European-Finnish (FIN)

AF:

0.00

AC:

AN:

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.00870

AC:

AN:

115

Other (OTH)

AF:

0.00

AC:

AN:

GnomAD4 genome

AF:

0.00634

AC:

718

AN:

113297

Hom.:

Cov.:

AF XY:

0.00601

AC XY:

213

AN XY:

35445

show subpopulations

African (AFR)

AF:

0.00131

AC:

AN:

31290

American (AMR)

AF:

0.00599

AC:

AN:

10852

Ashkenazi Jewish (ASJ)

AF:

0.00789

AC:

AN:

2662

East Asian (EAS)

AF:

0.00

AC:

AN:

3557

South Asian (SAS)

AF:

0.000356

AC:

AN:

2808

European-Finnish (FIN)

AF:

0.00728

AC:

AN:

6320

Middle Eastern (MID)

AF:

0.00461

AC:

AN:

217

European-Non Finnish (NFE)

AF:

0.00997

AC:

532

AN:

53351

Other (OTH)

AF:

0.00707

AC:

AN:

1556

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

103

129

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.0107

Hom.:

Bravo

AF:

0.00619

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

May 09, 2014

RettBASE

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:curation

Benign variation, found in normal male controls

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Benign:2

May 22, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

CDKL5 disorder

Benign:1

Jun 28, 2024

Centre for Population Genomics, CPG

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:curation

This variant has been collected from RettBASE and curated to current modified ACMG/AMP criteria. Based on the classification scheme defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like Disorders Specifications to the ACMG/AMP Variant Interpretation Guidelines VCEP 3.0, this variant is classified as benign. At least the following criteria are met: The allele frequency of this variant in at least one population in gnomAD v3 is higher than the 0.03% threshold defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like Disorders VCEP 3.0 (BA1).

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

6.6

(source)

DANN

Benign

0.87

PhyloP100

0.20

PromoterAI

0.044

Neutral

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over