NM_001323289.2:c.2372A>C

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001323289.2(CDKL5):c.2372A>C(p.Gln791Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0439 in 1,127,311 control chromosomes in the GnomAD database, including 931 homozygotes. There are 14,285 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.032 ( 65 hom., 938 hem., cov: 23)

Exomes 𝑓: 0.045 ( 866 hom. 13347 hem. )

Consequence

CDKL5
NM_001323289.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: 7.36

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.007584989).

BP6

Variant X-18619962-A-C is Benign according to our data. Variant chrX-18619962-A-C is described in ClinVar as [Benign]. Clinvar id is 136713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-18619962-A-C is described in Lovd as [Benign].

BA1

GnomAdExome4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0523 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDKL5	NM_001323289.2 link	c.2372A>C	p.Gln791Pro	missense_variant	Exon 16 of 18	ENST00000623535.2	NP_001310218.1	O76039-2
CDKL5	NM_001037343.2 link	c.2372A>C	p.Gln791Pro	missense_variant	Exon 17 of 22		NP_001032420.1	O76039-1
CDKL5	NM_003159.3 link	c.2372A>C	p.Gln791Pro	missense_variant	Exon 16 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.2372A>C	p.Gln791Pro	missense_variant	Exon 16 of 18	1	NM_001323289.2	ENSP00000485244.1		O76039-2

Frequencies

GnomAD3 genomes

AF:

0.0320

AC:

3600

AN:

112544

Hom.:

Cov.:

AF XY:

0.0270

AC XY:

938

AN XY:

34680

show subpopulations

Gnomad AFR

AF:

0.00696

Gnomad AMI

AF:

0.00871

Gnomad AMR

AF:

0.0248

Gnomad ASJ

AF:

0.0649

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0103

Gnomad FIN

AF:

0.0187

Gnomad MID

AF:

0.0126

Gnomad NFE

AF:

0.0515

Gnomad OTH

AF:

0.0331

GnomAD3 exomes

AF:

0.0313

AC:

5337

AN:

170666

Hom.:

AF XY:

0.0311

AC XY:

1792

AN XY:

57712

show subpopulations

Gnomad AFR exome

AF:

0.00564

Gnomad AMR exome

AF:

0.0144

Gnomad ASJ exome

AF:

0.0635

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0117

Gnomad FIN exome

AF:

0.0212

Gnomad NFE exome

AF:

0.0502

Gnomad OTH exome

AF:

0.0318

GnomAD4 exome

AF:

0.0452

AC:

45855

AN:

1014712

Hom.:

866

Cov.:

AF XY:

0.0448

AC XY:

13347

AN XY:

298150

show subpopulations

Gnomad4 AFR exome

AF:

0.00529

Gnomad4 AMR exome

AF:

0.0149

Gnomad4 ASJ exome

AF:

0.0656

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0134

Gnomad4 FIN exome

AF:

0.0217

Gnomad4 NFE exome

AF:

0.0527

Gnomad4 OTH exome

AF:

0.0420

GnomAD4 genome

AF:

0.0320

AC:

3602

AN:

112599

Hom.:

Cov.:

AF XY:

0.0270

AC XY:

938

AN XY:

34745

show subpopulations

Gnomad4 AFR

AF:

0.00695

Gnomad4 AMR

AF:

0.0248

Gnomad4 ASJ

AF:

0.0649

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.0103

Gnomad4 FIN

AF:

0.0187

Gnomad4 NFE

AF:

0.0516

Gnomad4 OTH

AF:

0.0327

Alfa

AF:

0.0486

Hom.:

2755

Bravo

AF:

0.0310

TwinsUK

AF:

0.0539

AC:

200

ALSPAC

AF:

0.0492

AC:

142

ESP6500AA

AF:

0.00576

AC:

ESP6500EA

AF:

0.0487

AC:

326

ExAC

AF:

0.0321

AC:

3881

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:8

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 23, 2012

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

May 15, 2014

RettBASE

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: curation

Common polymorphism -

Feb 13, 2015

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 20, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Developmental and epileptic encephalopathy, 2

Benign:1

Jul 22, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

CDKL5 disorder

Benign:1

Sep 16, 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). -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

History of neurodevelopmental disorder

Benign:1

Jun 25, 2015

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

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

Benign:1

Feb 04, 2025

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

0.12

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.27

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.059

T;T;T;.

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.93

.;D;D;D

MetaRNN

Benign

0.0076

T;T;T;T

MetaSVM

Uncertain

-0.27

MutationAssessor

Uncertain

2.0

M;.;M;M

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-1.6

N;.;N;.

REVEL

Uncertain

0.34

Sift

Pathogenic

0.0

D;.;D;.

Sift4G

Uncertain

0.0060

D;.;D;D

Polyphen

1.0

D;.;D;.

Vest4

0.64

MPC

0.52

ClinPred

0.026

GERP RS

5.5

Varity_R

0.79

gMVP

0.34

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