Genetic Variant CDKL3:p.Met394Leu (chr5-134308322-T-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001113575.2(CDKL3):c.1180A>T(p.Met394Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,634 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M394V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

CDKL3
NM_001113575.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.62

Publications

0 publications found

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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.029227704).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001113575.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CDKL3	NM_001113575.2	MANE Select	c.1180A>T	p.Met394Leu	missense	Exon 9 of 13	NP_001107047.1	Q8IVW4-1
CDKL3	NM_016508.4		c.1180A>T	p.Met394Leu	missense	Exon 9 of 9	NP_057592.2	Q8IVW4-2
CDKL3	NM_001349363.2		c.613A>T	p.Met205Leu	missense	Exon 6 of 11	NP_001336292.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CDKL3	ENST00000265334.9	TSL:1 MANE Select	c.1180A>T	p.Met394Leu	missense	Exon 9 of 13	ENSP00000265334.4	Q8IVW4-1
CDKL3	ENST00000523832.1	TSL:1	c.1180A>T	p.Met394Leu	missense	Exon 8 of 8	ENSP00000430496.1	Q8IVW4-2
CDKL3	ENST00000519312.5	TSL:1	n.*138A>T		non_coding_transcript_exon	Exon 5 of 9	ENSP00000427738.1	E5RGK4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461634

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727098

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39686

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53398

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111824

Other (OTH)

AF:

0.00

AC:

AN:

60370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.62

CADD

Benign

0.0020

(source)

DANN

Benign

0.28

DEOGEN2

Benign

0.0026

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.9

FATHMM_MKL

Benign

0.0077

LIST_S2

Benign

0.47

M_CAP

Benign

0.017

MetaRNN

Benign

0.029

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.11

PhyloP100

-2.6

PrimateAI

Benign

0.27

PROVEAN

Benign

-0.030

REVEL

Benign

0.023

Sift

Benign

0.79

Sift4G

Benign

0.84

Polyphen

0.0

Vest4

0.13

MutPred

0.16

Loss of methylation at K399 (P = 0.0601)

MVP

0.11

MPC

0.019

ClinPred

0.020

GERP RS

-11

Varity_R

0.078

gMVP

0.075

Mutation Taster

=96/4

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over