Genetic Variant NM_001113575.2:c.1486G>A (chr5-134304540-C-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_001113575.2(CDKL3):c.1486G>A(p.Glu496Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000242 in 1,610,364 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000024 ( 0 hom. )

Consequence

CDKL3
NM_001113575.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.24

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: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.35474646).

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.1486G>A	p.Glu496Lys	missense	Exon 11 of 13	NP_001107047.1	Q8IVW4-1
CDKL3	NM_001349363.2		c.919G>A	p.Glu307Lys	missense	Exon 8 of 11	NP_001336292.1
CDKL3	NM_001300853.2		c.919G>A	p.Glu307Lys	missense	Exon 10 of 13	NP_001287782.1	B4DX41

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CDKL3	ENST00000265334.9	TSL:1 MANE Select	c.1486G>A	p.Glu496Lys	missense	Exon 11 of 13	ENSP00000265334.4	Q8IVW4-1
CDKL3	ENST00000519312.5	TSL:1	n.*444G>A		non_coding_transcript_exon	Exon 7 of 9	ENSP00000427738.1	E5RGK4
CDKL3	ENST00000519312.5	TSL:1	n.*444G>A		3_prime_UTR	Exon 7 of 9	ENSP00000427738.1	E5RGK4

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152034

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000197

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000410

AC:

AN:

243794

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000298

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000240

AC:

AN:

1458330

Hom.:

Cov.:

AF XY:

0.0000193

AC XY:

AN XY:

725272

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33376

American (AMR)

AF:

0.0000678

AC:

AN:

44254

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25998

East Asian (EAS)

AF:

0.00

AC:

AN:

39580

South Asian (SAS)

AF:

0.00

AC:

AN:

85526

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52974

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.0000279

AC:

AN:

1110594

Other (OTH)

AF:

0.0000166

AC:

AN:

60266

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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:

0.0000263

AC:

AN:

152034

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74266

show subpopulations

African (AFR)

AF:

0.0000242

AC:

AN:

41404

American (AMR)

AF:

0.000197

AC:

AN:

15244

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10578

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68006

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.550

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000416

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.087

BayesDel_addAF

Uncertain

0.089

BayesDel_noAF

Benign

-0.11

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.022

Eigen

Uncertain

0.38

Eigen_PC

Uncertain

0.44

FATHMM_MKL

Benign

0.71

LIST_S2

Uncertain

0.86

M_CAP

Benign

0.052

MetaRNN

Benign

0.35

MetaSVM

Uncertain

-0.15

MutationAssessor

Benign

1.7

PhyloP100

4.2

PrimateAI

Benign

0.44

PROVEAN

Benign

-1.4

REVEL

Benign

0.18

Sift

Uncertain

0.017

Sift4G

Benign

0.26

Polyphen

0.79

Vest4

0.50

MutPred

0.20

Gain of ubiquitination at E496 (P = 0.0037)

MVP

0.71

MPC

0.052

ClinPred

0.84

GERP RS

5.3

PromoterAI

0.0043

Neutral

(source)

Varity_R

0.24

gMVP

0.21

Mutation Taster

=69/31

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over