Genetic Variant CDKL3:p.Arg464Cys (chr5-134306677-G-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001113575.2(CDKL3):c.1390C>T(p.Arg464Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000146 in 1,563,788 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00015 ( 1 hom. )

Consequence

CDKL3
NM_001113575.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.567

Variant links:

Genes affected

CDKL3 (HGNC:15483): (cyclin dependent kinase like 3) The protein encoded by this gene is a member of cyclin-dependent protein kinase (CDK) family. CDK family members are highly similar to the gene products of Saccharomyces cerevisiae cdc28, and Schizosaccharomyces pombe cdc2, and are known to be important regulators of cell cycle progression. This gene was identified as a gene absent in leukemic patients with chromosome 5q deletion. This loss may be an important determinant of dysmyelopoiesis. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]

CDKL3 links:

ENSG00000273345 (HGNC:):

ENSG00000273345 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.049702168).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDKL3	NM_001113575.2 link	c.1390C>T	p.Arg464Cys	missense_variant	Exon 10 of 13	ENST00000265334.9	NP_001107047.1	Q8IVW4-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDKL3	ENST00000265334.9 link	c.1390C>T	p.Arg464Cys	missense_variant	Exon 10 of 13	1	NM_001113575.2	ENSP00000265334.4		Q8IVW4-1
ENSG00000273345	ENST00000703317.1 link	n.86-3990C>T		intron_variant	Intron 2 of 9			ENSP00000515260.1		A0A8V8TQA6

Frequencies

GnomAD3 genomes

AF:

0.000141

AC:

AN:

149280

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000739

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000539

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000196

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000133

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000142

AC:

AN:

204072

Hom.:

AF XY:

0.000143

AC XY:

AN XY:

112274

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000727

Gnomad ASJ exome

AF:

0.000118

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000481

Gnomad NFE exome

AF:

0.0000821

Gnomad OTH exome

AF:

0.000422

GnomAD4 exome

AF:

0.000147

AC:

208

AN:

1414442

Hom.:

Cov.:

AF XY:

0.000145

AC XY:

102

AN XY:

703450

show subpopulations

Gnomad4 AFR exome

AF:

0.0000337

Gnomad4 AMR exome

AF:

0.000635

Gnomad4 ASJ exome

AF:

0.0000406

Gnomad4 EAS exome

AF:

0.0000273

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000189

Gnomad4 NFE exome

AF:

0.000159

Gnomad4 OTH exome

AF:

0.000154

GnomAD4 genome

AF:

0.000141

AC:

AN:

149346

Hom.:

Cov.:

AF XY:

0.000124

AC XY:

AN XY:

72566

show subpopulations

Gnomad4 AFR

AF:

0.0000737

Gnomad4 AMR

AF:

0.000538

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000196

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000133

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000165

Hom.:

Bravo

AF:

0.000208

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.000108

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 22, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1390C>T (p.R464C) alteration is located in exon 10 (coding exon 9) of the CDKL3 gene. This alteration results from a C to T substitution at nucleotide position 1390, causing the arginine (R) at amino acid position 464 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.084

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.29

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.015

T;.;.

Eigen

Benign

-0.31

Eigen_PC

Benign

-0.30

FATHMM_MKL

Benign

0.31

LIST_S2

Benign

0.78

T;T;T

M_CAP

Uncertain

0.21

MetaRNN

Benign

0.050

T;T;T

MetaSVM

Uncertain

-0.28

MutationAssessor

Benign

1.8

L;.;.

PrimateAI

Benign

0.26

PROVEAN

Benign

-1.1

N;N;N

REVEL

Benign

0.071

Sift

Uncertain

0.0040

D;D;D

Sift4G

Benign

0.16

T;D;T

Polyphen

1.0

D;D;.

Vest4

0.27

MVP

0.73

MPC

0.15

ClinPred

0.18

GERP RS

3.1

Varity_R

0.14

gMVP

0.093

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.11

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