rs143243059

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BS1BP4

This summary comes from the ClinGen Evidence Repository: RS1 (NM_000330.4) and an alternative transcript of CDKL5 (NM_003159.2) are overlapping transcripts; however, these variants are in the noncoding 3' region of the main CDKL5 transcript (NM_001323289.2). The allele frequency of the c.2933T>G (p.Leu978Arg) variant in the CDKL5 transcript (NM_003159.2) (RS1 c.185-3213A>C) is 0.01184% in the European (non-Finnish) sub population in gnomAD, which is high enough to meet the BS1 criteria based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BS1). Computational analysis prediction tools suggest that the p.Leu978Arg variant does not have a deleterious impact; however this information does not predict clinical significance on its own (BP4). In summary, the p.Leu978Arg variant in CDKL5 is classified as likely benign based on the ACMG/AMP criteria (BS1, BP4). LINK:https://erepo.genome.network/evrepo/ui/classification/CA10360748/MONDO:0100039/016

Frequency

Genomes: 𝑓 0.000080 ( 0 hom., 2 hem., cov: 24)

Exomes 𝑓: 0.000097 ( 0 hom. 24 hem. )

Consequence

CDKL5
ENST00000379989.6 missense

Scores

Clinical Significance

Likely benign reviewed by expert panel U:1B:3

Conservation

PhyloP100: 0.361

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: Likely_benign. The variant received -5 ACMG points.

BP4

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

BS1

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.185-3213A>C		intron_variant	Intron 3 of 5	ENST00000379984.4	NP_000321.1	O15537
CDKL5	NM_001037343.2 link	c.2933T>G	p.Leu978Arg	missense_variant	Exon 21 of 22		NP_001032420.1	O76039-1
CDKL5	NM_003159.3 link	c.2933T>G	p.Leu978Arg	missense_variant	Exon 20 of 21		NP_003150.1	O76039-1
RS1	XM_047442337.1 link	c.-162A>C		5_prime_UTR_variant	Exon 1 of 4		XP_047298293.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RS1	ENST00000379984.4 link	c.185-3213A>C		intron_variant	Intron 3 of 5	1	NM_000330.4	ENSP00000369320.3		O15537

Frequencies

GnomAD3 genomes

AF:

0.0000799

AC:

AN:

112571

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:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000169

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000273

AC:

AN:

183424

AF XY:

0.0000442

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:

0.0000488

Gnomad OTH exome

AF:

0.000221

GnomAD4 exome

AF:

0.0000974

AC:

107

AN:

1098175

Hom.:

Cov.:

AF XY:

0.0000660

AC XY:

AN XY:

363531

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26401

American (AMR)

AF:

0.00

AC:

AN:

35206

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19386

East Asian (EAS)

AF:

0.00

AC:

AN:

30206

South Asian (SAS)

AF:

0.00

AC:

AN:

54146

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40523

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4136

European-Non Finnish (NFE)

AF:

0.000115

AC:

AN:

842075

Other (OTH)

AF:

0.000217

AC:

AN:

46096

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

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:

0.0000799

AC:

AN:

112571

Hom.:

Cov.:

AF XY:

0.0000576

AC XY:

AN XY:

34717

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30974

American (AMR)

AF:

0.00

AC:

AN:

10684

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2657

East Asian (EAS)

AF:

0.00

AC:

AN:

3592

South Asian (SAS)

AF:

0.00

AC:

AN:

2730

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6200

Middle Eastern (MID)

AF:

0.00

AC:

AN:

238

European-Non Finnish (NFE)

AF:

0.000169

AC:

AN:

53289

Other (OTH)

AF:

0.00

AC:

AN:

1523

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

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:

0.000174

Hom.:

Bravo

AF:

0.0000529

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000297

AC:

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:1Benign:3

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Sep 29, 2017

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

CDKL5 disorder

Benign:1

Feb 20, 2023

ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel

Significance:Likely benign

Review Status:reviewed by expert panel

Collection Method:curation

RS1 (NM_000330.4) and an alternative transcript of CDKL5 (NM_003159.2) are overlapping transcripts; however, these variants are in the noncoding 3' region of the main CDKL5 transcript (NM_001323289.2). The allele frequency of the c.2933T>G (p.Leu978Arg) variant in the CDKL5 transcript (NM_003159.2) (RS1 c.185-3213A>C) is 0.01184% in the European (non-Finnish) sub population in gnomAD, which is high enough to meet the BS1 criteria based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BS1). Computational analysis prediction tools suggest that the p.Leu978Arg variant does not have a deleterious impact; however this information does not predict clinical significance on its own (BP4). In summary, the p.Leu978Arg variant in CDKL5 is classified as likely benign based on the ACMG/AMP criteria (BS1, BP4). -

not provided

Benign:1

Oct 30, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Benign:1

Oct 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.096

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.44

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.029

T;T

FATHMM_MKL

Benign

0.035

LIST_S2

Benign

0.37

.;T

M_CAP

Uncertain

0.27

MetaRNN

Benign

0.21

T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.0

N;N

PhyloP100

0.36

PrimateAI

Benign

0.35

PROVEAN

Benign

0.070

N;N

REVEL

Benign

0.15

Sift

Uncertain

0.0020

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

0.0

B;B

Vest4

0.52

MVP

0.36

MPC

1.1

ClinPred

0.058

GERP RS

-3.2

Varity_R

0.22

gMVP

0.50

Mutation Taster

=99/1

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