rs267608436

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP5BS2

This summary comes from the ClinGen Evidence Repository: The p.Arg65Gln variant in CDKL5 is present in 2 female and 1 male individuals in gnomAD (0.002%) (not sufficient to meet BS1 criteria). The p.Arg65Gln variant is observed in at least 2 unaffected individuals (internal database) (BS2). The p.Arg65Gln variant is found in 2 patients with an alternate molecular basis of disease (internal database) (BP5). In summary, the p.Arg65Gln variant in CDKL5 is classified as likely benign based on the ACMG/AMP criteria (BS2, BP5). LINK:https://erepo.genome.network/evrepo/ui/classification/CA170462/MONDO:0100039/034

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 1 hem., cov: 23)

Exomes 𝑓: 0.000016 ( 0 hom. 8 hem. )

Consequence

CDKL5
NM_001323289.2 missense

Scores

Clinical Significance

Likely benign reviewed by expert panel B:6

Conservation

PhyloP100: 10.0

Publications

6 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: Likely_benign. The variant received -5 ACMG points.

BP5

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
CDKL5	NM_001323289.2 link	c.194G>A	p.Arg65Gln	missense_variant	Exon 5 of 18	ENST00000623535.2	NP_001310218.1	O76039-2
CDKL5	NM_001037343.2 link	c.194G>A	p.Arg65Gln	missense_variant	Exon 6 of 22		NP_001032420.1	O76039-1
CDKL5	NM_003159.3 link	c.194G>A	p.Arg65Gln	missense_variant	Exon 5 of 21		NP_003150.1	O76039-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDKL5	ENST00000623535.2 link	c.194G>A	p.Arg65Gln	missense_variant	Exon 5 of 18	1	NM_001323289.2	ENSP00000485244.1		O76039-2

Frequencies

GnomAD3 genomes

AF:

0.0000179

AC:

AN:

111779

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:

0.0000376

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000164

AC:

AN:

182997

AF XY:

0.0000148

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000365

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000245

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000165

AC:

AN:

1093207

Hom.:

Cov.:

AF XY:

0.0000223

AC XY:

AN XY:

358913

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26282

American (AMR)

AF:

0.0000284

AC:

AN:

35165

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19334

East Asian (EAS)

AF:

0.00

AC:

AN:

30154

South Asian (SAS)

AF:

0.00

AC:

AN:

54021

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40511

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4114

European-Non Finnish (NFE)

AF:

0.0000203

AC:

AN:

837697

Other (OTH)

AF:

0.00

AC:

AN:

45929

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

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:

0.0000179

AC:

AN:

111779

Hom.:

Cov.:

AF XY:

0.0000294

AC XY:

AN XY:

34005

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30776

American (AMR)

AF:

0.00

AC:

AN:

10514

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2649

East Asian (EAS)

AF:

0.00

AC:

AN:

3556

South Asian (SAS)

AF:

0.00

AC:

AN:

2686

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6001

Middle Eastern (MID)

AF:

0.00

AC:

AN:

238

European-Non Finnish (NFE)

AF:

0.0000376

AC:

AN:

53161

Other (OTH)

AF:

0.00

AC:

AN:

1511

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.0000546

EpiControl

AF:

0.000119

ClinVar

Significance: Likely benign

Submissions summary: Benign:6

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

CDKL5 disorder

Benign:2

Aug 23, 2023

ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel

Significance:Likely benign

Review Status:reviewed by expert panel

Collection Method:curation

The p.Arg65Gln variant in CDKL5 is present in 2 female and 1 male individuals in gnomAD (0.002%) (not sufficient to meet BS1 criteria). The p.Arg65Gln variant is observed in at least 2 unaffected individuals (internal database) (BS2). The p.Arg65Gln variant is found in 2 patients with an alternate molecular basis of disease (internal database) (BP5). In summary, the p.Arg65Gln variant in CDKL5 is classified as likely benign based on the ACMG/AMP criteria (BS2, BP5). -

Jul 02, 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 population databases (gnomAD , Turkish Variome) is between 0.008% and 0.03% (BS1). The variant is observed in at least 2 individuals with no features of CDKL5 disorder (BS2). PubMed: 17993579 Variation ID: 143789 -

not specified

Benign:1

May 09, 2014

RettBASE

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:curation

Reported in paper as c.193C>A, but chromatogram shows c.194G>A; found in unaffected male family member; however, In silico prediction: SIFT = deleterious, MutationTaster = disease-causing, PolyPhen2 = probably damaging, AlignGVGD = pathogenic (C35) -

not provided

Benign:1

May 05, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 17993579) -

CDKL5-related disorder

Benign:1

Apr 08, 2021

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

May 14, 2024

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

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Pathogenic

0.26

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.20

T;T;.;T;.;.;.

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

.;D;D;D;D;D;D

M_CAP

Pathogenic

0.79

MetaRNN

Pathogenic

0.97

D;D;D;D;D;D;D

MetaSVM

Benign

-0.36

MutationAssessor

Benign

0.41

N;.;.;N;.;.;N

PhyloP100

PrimateAI

Pathogenic

0.90

PROVEAN

Uncertain

-3.9

D;.;.;D;.;.;.

REVEL

Pathogenic

0.68

Sift

Benign

0.031

D;.;.;D;.;.;.

Sift4G

Benign

0.078

T;.;.;T;T;D;D

Polyphen

1.0

D;.;.;D;.;.;.

Vest4

0.91

MutPred

0.86

Loss of MoRF binding (P = 0.0201);Loss of MoRF binding (P = 0.0201);Loss of MoRF binding (P = 0.0201);Loss of MoRF binding (P = 0.0201);Loss of MoRF binding (P = 0.0201);Loss of MoRF binding (P = 0.0201);Loss of MoRF binding (P = 0.0201);

MVP

0.92

MPC

2.4

ClinPred

0.80

GERP RS

5.7

Varity_R

0.86

gMVP

0.93

Mutation Taster

=67/33

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over