rs587783160

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BS2BP4

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 non-coding 3' region of the main CDKL5 transcript (NM_ 001323289.2). The c.2739 G>C (p.Gln913His) variant in CDKL5 transcript (NM_003159.3) (RS1 c.326+1159 C>G) is observed in at least 2 unaffected individuals (GeneDx and Invitae internal databases) (BS2). Computational analysis prediction tools suggest that the c.2739 G>C variant does not have a deleterious impact; however this information does not predict clinical significance on its own (BP4). In summary, the c.2739 G>C variant in the alternate CDKL5 transcript (NM_003159.3) is classified as likely benign based on the ACMG/AMP criteria (BS2, BP4). LINK:https://erepo.genome.network/evrepo/ui/classification/CA294768/MONDO:0100039/034

Frequency

Genomes: 𝑓 0.0000089 ( 0 hom., 1 hem., cov: 22)

Exomes 𝑓: 0.000075 ( 0 hom. 26 hem. )

Consequence

CDKL5
ENST00000379989.6 missense

Scores

Clinical Significance

Likely benign reviewed by expert panel U:1B:4

Conservation

PhyloP100: 0.206

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 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.

BS2

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.326+1159C>G		intron_variant	Intron 4 of 5	ENST00000379984.4	NP_000321.1	O15537
CDKL5	NM_001037343.2 link	c.2739G>C	p.Gln913His	missense_variant	Exon 20 of 22		NP_001032420.1	O76039-1
CDKL5	NM_003159.3 link	c.2739G>C	p.Gln913His	missense_variant	Exon 19 of 21		NP_003150.1	O76039-1
RS1	XM_047442337.1 link	c.230+1159C>G		intron_variant	Intron 2 of 3		XP_047298293.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CDKL5	ENST00000379989.6 link	c.2739G>C	p.Gln913His	missense_variant	Exon 20 of 22	1		ENSP00000369325.3	O76039-1
CDKL5	ENST00000379996.7 link	c.2739G>C	p.Gln913His	missense_variant	Exon 19 of 21	1		ENSP00000369332.3	O76039-1
RS1	ENST00000379984.4 link	c.326+1159C>G		intron_variant	Intron 4 of 5	1	NM_000330.4	ENSP00000369320.3	O15537
RS1	ENST00000476595.1 link	n.817+1159C>G		intron_variant	Intron 3 of 4	1

Frequencies

GnomAD3 genomes

AF:

0.00000893

AC:

AN:

111987

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:

0.0000188

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000110

AC:

AN:

181642

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:

0.0000250

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000747

AC:

AN:

1098221

Hom.:

Cov.:

AF XY:

0.0000715

AC XY:

AN XY:

363577

show subpopulations

African (AFR)

AF:

0.0000379

AC:

AN:

26402

American (AMR)

AF:

0.00

AC:

AN:

35206

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19384

East Asian (EAS)

AF:

0.00

AC:

AN:

30204

South Asian (SAS)

AF:

0.00

AC:

AN:

54148

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40526

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4137

European-Non Finnish (NFE)

AF:

0.0000950

AC:

AN:

842119

Other (OTH)

AF:

0.0000217

AC:

AN:

46095

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

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:

0.00000893

AC:

AN:

111987

Hom.:

Cov.:

AF XY:

0.0000293

AC XY:

AN XY:

34159

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30783

American (AMR)

AF:

0.00

AC:

AN:

10547

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2649

East Asian (EAS)

AF:

0.00

AC:

AN:

3588

South Asian (SAS)

AF:

0.00

AC:

AN:

2676

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6131

Middle Eastern (MID)

AF:

0.00

AC:

AN:

240

European-Non Finnish (NFE)

AF:

0.0000188

AC:

AN:

53205

Other (OTH)

AF:

0.00

AC:

AN:

1487

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:

0.00000824

AC:

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:1Benign:4

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Developmental and epileptic encephalopathy, 2

Uncertain:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

CDKL5 disorder

Benign:1

Apr 14, 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 non-coding 3' region of the main CDKL5 transcript (NM_ 001323289.2). The c.2739 G>C (p.Gln913His) variant in CDKL5 transcript (NM_003159.3) (RS1 c.326+1159 C>G) is observed in at least 2 unaffected individuals (GeneDx and Invitae internal databases) (BS2). Computational analysis prediction tools suggest that the c.2739 G>C variant does not have a deleterious impact; however this information does not predict clinical significance on its own (BP4). In summary, the c.2739 G>C variant in the alternate CDKL5 transcript (NM_003159.3) is classified as likely benign based on the ACMG/AMP criteria (BS2, BP4). -

not provided

Benign:1

Apr 02, 2018

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

CDKL5-related disorder

Benign:1

Sep 25, 2023

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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

Benign:1

Oct 03, 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

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.75

CADD

Benign

7.0

(source)

DANN

Benign

0.91

DEOGEN2

Benign

0.018

T;T

FATHMM_MKL

Benign

0.014

LIST_S2

Benign

0.31

.;T

M_CAP

Uncertain

0.20

MetaRNN

Benign

0.098

T;T

MetaSVM

Benign

-0.88

MutationAssessor

Benign

0.0

N;N

PhyloP100

0.21

PrimateAI

Benign

0.40

PROVEAN

Benign

0.31

N;N

REVEL

Benign

0.086

Sift

Uncertain

0.0020

D;D

Sift4G

Benign

0.087

T;T

Polyphen

0.68

P;P

Vest4

0.063

MutPred

0.19

Gain of catalytic residue at Q913 (P = 0.0293);Gain of catalytic residue at Q913 (P = 0.0293);

MVP

0.49

MPC

0.45

ClinPred

0.070

GERP RS

1.0

Varity_R

0.098

gMVP

0.20

Mutation Taster

=95/5

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