ENST00000379989.6:c.2896G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BS2_SupportingBP5BA1BP4

This summary comes from the ClinGen Evidence Repository: The allele frequency of the p.Val966Ile variant in CDKL5 is 0.03% in South Asian sub population in gnomAD, which is high enough to be classified as benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BA1). The p.Val966Ile variant is observed in at least 1 unaffected individual (internal database) (BS2_supporting). Computational analysis prediction tools suggest that the p.Val966Ile variant does not have a deleterious impact; however this information does not predict clinical significance on its own (BP4). The p.Val966Ile variant is found in a patient with an alternate molecular basis of disease (internal database) (BP5). In summary, the p.Val966Ile variant in CDKL5 is classified as benign based on the ACMG/AMP criteria applied (BA1, BS2_supporting, BP4, BP5). LINK:https://erepo.genome.network/evrepo/ui/classification/CA209185/MONDO:0100039/016

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 1 hem., cov: 24)

Exomes 𝑓: 0.000046 ( 0 hom. 22 hem. )

Consequence

CDKL5
ENST00000379989.6 missense

Scores

Clinical Significance

Benign reviewed by expert panel B:6

Conservation

PhyloP100: -0.0330

Publications

1 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 links:

RS1 (HGNC:10457): (retinoschisin 1) This gene encodes an extracellular protein that plays a crucial role in the cellular organization of the retina. The encoded protein is assembled and secreted from photoreceptors and bipolar cells as a homo-oligomeric protein complex. Mutations in this gene are responsible for X-linked retinoschisis, a common, early-onset macular degeneration in males that results in a splitting of the inner layers of the retina and severe loss in vision. [provided by RefSeq, Oct 2008]

RS1 Gene-Disease associations (from GenCC):

retinoschisis
Inheritance: XL Classification: DEFINITIVE Submitted by: G2P
X-linked retinoschisis
Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, ClinGen

RS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -11 ACMG points.

BP4

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

BP5

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

BS2

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

BA1

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RS1	NM_000330.4 link	c.185-3176C>T		intron_variant	Intron 3 of 5	ENST00000379984.4	NP_000321.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RS1	ENST00000379984.4 link	c.185-3176C>T		intron_variant	Intron 3 of 5	1	NM_000330.4	ENSP00000369320.3

Frequencies

GnomAD3 genomes

AF:

0.0000178

AC:

AN:

112374

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:

0.000368

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000188

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000327

AC:

AN:

183481

AF XY:

0.0000589

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000464

AC:

AN:

1098012

Hom.:

Cov.:

AF XY:

0.0000605

AC XY:

AN XY:

363382

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26399

American (AMR)

AF:

0.00

AC:

AN:

35205

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19386

East Asian (EAS)

AF:

0.00

AC:

AN:

30203

South Asian (SAS)

AF:

0.000425

AC:

AN:

54144

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40516

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4137

European-Non Finnish (NFE)

AF:

0.0000321

AC:

AN:

841931

Other (OTH)

AF:

0.0000217

AC:

AN:

46091

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

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:

0.0000178

AC:

AN:

112374

Hom.:

Cov.:

AF XY:

0.0000290

AC XY:

AN XY:

34520

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

30917

American (AMR)

AF:

0.00

AC:

AN:

10650

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2653

East Asian (EAS)

AF:

0.00

AC:

AN:

3573

South Asian (SAS)

AF:

0.000368

AC:

AN:

2716

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6184

Middle Eastern (MID)

AF:

0.00

AC:

AN:

239

European-Non Finnish (NFE)

AF:

0.0000188

AC:

AN:

53237

Other (OTH)

AF:

0.00

AC:

AN:

1517

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 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: 0.375

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.:

Bravo

AF:

0.0000113

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

CDKL5 disorder

Benign:2

Jul 12, 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 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).

Mar 26, 2021

ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel

Significance:Benign

Review Status:reviewed by expert panel

Collection Method:curation

The allele frequency of the p.Val966Ile variant in CDKL5 is 0.03% in South Asian sub population in gnomAD, which is high enough to be classified as benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BA1). The p.Val966Ile variant is observed in at least 1 unaffected individual (internal database) (BS2_supporting). Computational analysis prediction tools suggest that the p.Val966Ile variant does not have a deleterious impact; however this information does not predict clinical significance on its own (BP4). The p.Val966Ile variant is found in a patient with an alternate molecular basis of disease (internal database) (BP5). In summary, the p.Val966Ile variant in CDKL5 is classified as benign based on the ACMG/AMP criteria applied (BA1, BS2_supporting, BP4, BP5).

not specified

Benign:1

Feb 04, 2015

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Developmental and epileptic encephalopathy, 2

Benign:1

May 28, 2019

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Benign:1

Jun 24, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 23756444, 23242510)

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

Benign:1

Jun 11, 2023

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

AlphaMissense

Benign

0.092

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.74

CADD

Benign

1.6

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.025

T;T

FATHMM_MKL

Benign

0.014

LIST_S2

Benign

0.0

.;T

M_CAP

Pathogenic

0.92

MetaRNN

Benign

0.13

T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.0

N;N

PhyloP100

-0.033

PrimateAI

Benign

0.31

PROVEAN

Benign

-0.040

N;N

REVEL

Benign

0.10

Sift

Benign

0.039

D;D

Sift4G

Pathogenic

0.0

D;D

Vest4

0.053

ClinPred

0.026

GERP RS

1.0

Varity_R

0.055

gMVP

0.034

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over