dbSNP rs141333215: CDKL4:p.Glu39Lys (chr2-39229418-C-T) – 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_001346911.1(CDKL4):c.115G>A(p.Glu39Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000716 in 1,612,340 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 0.00082 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00071 ( 0 hom. )

Consequence

CDKL4
NM_001346911.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.50

Variant links:

Genes affected

CDKL4 (HGNC:19287): (cyclin dependent kinase like 4) Predicted to enable cyclin-dependent protein serine/threonine kinase activity. Predicted to be involved in protein phosphorylation. Predicted to be located in cytoplasm. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

CDKL4 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=0.03547111).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	Protein	UniProt
CDKL4	NM_001346911.1 link	c.115G>A	p.Glu39Lys	missense_variant	Exon 1 of 9	NP_001333840.1	Q5MAI5-1
CDKL4	NM_001397900.1 link	c.115G>A	p.Glu39Lys	missense_variant	Exon 2 of 10	NP_001384829.1
CDKL4	NM_001009565.2 link	c.115G>A	p.Glu39Lys	missense_variant	Exon 1 of 8	NP_001009565.1	Q5MAI5-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDKL4	ENST00000451199.7 link	c.115G>A	p.Glu39Lys	missense_variant	Exon 2 of 10	2		ENSP00000389833.2		H7BZI6

Frequencies

GnomAD3 genomes

AF:

0.000821

AC:

125

AN:

152220

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000458

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000659

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00147

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000697

AC:

174

AN:

249724

Hom.:

AF XY:

0.000763

AC XY:

103

AN XY:

134930

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.0000585

Gnomad ASJ exome

AF:

0.00249

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000833

Gnomad NFE exome

AF:

0.00110

Gnomad OTH exome

AF:

0.000328

GnomAD4 exome

AF:

0.000705

AC:

1030

AN:

1460002

Hom.:

Cov.:

AF XY:

0.000708

AC XY:

514

AN XY:

726178

show subpopulations

Gnomad4 AFR exome

AF:

0.0000898

Gnomad4 AMR exome

AF:

0.000158

Gnomad4 ASJ exome

AF:

0.00261

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000117

Gnomad4 FIN exome

AF:

0.000937

Gnomad4 NFE exome

AF:

0.000775

Gnomad4 OTH exome

AF:

0.000646

GnomAD4 genome

AF:

0.000821

AC:

125

AN:

152338

Hom.:

Cov.:

AF XY:

0.000819

AC XY:

AN XY:

74494

show subpopulations

Gnomad4 AFR

AF:

0.0000962

Gnomad4 AMR

AF:

0.000457

Gnomad4 ASJ

AF:

0.00173

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000659

Gnomad4 NFE

AF:

0.00147

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.00118

Hom.:

Bravo

AF:

0.000703

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00140

AC:

ExAC

AF:

0.000675

AC:

EpiCase

AF:

0.000982

EpiControl

AF:

0.00113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 19, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.115G>A (p.E39K) alteration is located in exon 1 (coding exon 1) of the CDKL4 gene. This alteration results from a G to A substitution at nucleotide position 115, causing the glutamic acid (E) at amino acid position 39 to be replaced by a lysine (K). 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

0.15

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.27

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.041

.;T

Eigen

Uncertain

0.30

Eigen_PC

Uncertain

0.29

FATHMM_MKL

Uncertain

0.93

LIST_S2

Pathogenic

0.97

D;D

M_CAP

Uncertain

0.13

MetaRNN

Benign

0.035

T;T

MetaSVM

Benign

-0.57

MutationAssessor

Benign

0.48

N;N

PrimateAI

Uncertain

0.65

PROVEAN

Uncertain

-3.9

D;D

REVEL

Benign

0.27

Sift

Uncertain

0.010

D;D

Sift4G

Uncertain

0.015

D;D

Polyphen

1.0

.;D

Vest4

0.33

MVP

0.67

MPC

0.58

ClinPred

0.18

GERP RS

4.5

Varity_R

0.57

gMVP

0.32

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