rs267608436

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 8P and 8B. PM1PM5PP3_StrongBP6_Very_Strong

The NM_001323289.2(CDKL5):c.194G>A(p.Arg65Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000166 in 1,204,986 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 9 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R65P) has been classified as Pathogenic.

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:5

Conservation

PhyloP100: 10.0

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM1

In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_001323289.2

PM5

Other missense variant is known to change same aminoacid residue: Variant chrX-18575402-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 1072615.Status of the report is criteria_provided_single_submitter, 1 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.965

BP6

Variant X-18575402-G-A is Benign according to our data. Variant chrX-18575402-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 143789.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
CDKL5	NM_001323289.2 linkuse as main transcript	c.194G>A	p.Arg65Gln	missense_variant	5/18	ENST00000623535.2
CDKL5	NM_001037343.2 linkuse as main transcript	c.194G>A	p.Arg65Gln	missense_variant	6/22
CDKL5	NM_003159.3 linkuse as main transcript	c.194G>A	p.Arg65Gln	missense_variant	5/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDKL5	ENST00000623535.2 linkuse as main transcript	c.194G>A	p.Arg65Gln	missense_variant	5/18	1	NM_001323289.2	P1	O76039-2

Frequencies

GnomAD3 genomes

AF:

0.0000179

AC:

AN:

111779

Hom.:

Cov.:

AF XY:

0.0000294

AC XY:

AN XY:

34005

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

GnomAD3 exomes

AF:

0.0000164

AC:

AN:

182997

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

67635

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 SAS 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

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000284

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000203

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000179

AC:

AN:

111779

Hom.:

Cov.:

AF XY:

0.0000294

AC XY:

AN XY:

34005

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000376

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000189

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.0000546

EpiControl

AF:

0.000119

ClinVar

Significance: Likely benign

Submissions summary: Benign:5

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Benign:1

Benign, no assertion criteria provided

curation

RettBASE

May 09, 2014

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) -

CDKL5 disorder

Benign:1

Likely benign, reviewed by expert panel

curation

ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel

Aug 23, 2023

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). -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

May 05, 2021

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

CDKL5-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 08, 2021

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 14, 2023

- -

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

Dann

Pathogenic

1.0

DEOGEN2

Benign

0.20

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

FATHMM_MKL

Pathogenic

0.99

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

MutationTaster

Benign

1.0

D;D

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over