Genetic Variant CDKL1:p.Asp41Glu (chr14-50395746-G-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_004196.7(CDKL1):c.123C>A(p.Asp41Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000682 in 1,613,758 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

CDKL1
NM_004196.7 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.02

Variant links:

Genes affected

CDKL1 (HGNC:1781): (cyclin dependent kinase like 1) This gene product is a member of a large family of CDC2-related serine/threonine protein kinases that accumulates primarily in the nucleus. [provided by RefSeq, Nov 2018]

CDKL1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.12226054).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDKL1	NM_004196.7 link	c.123C>A	p.Asp41Glu	missense_variant	Exon 2 of 10	ENST00000395834.6	NP_004187.3	Q00532

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CDKL1	ENST00000395834.6 link	c.123C>A	p.Asp41Glu	missense_variant	Exon 2 of 10	1	NM_004196.7	ENSP00000379176.2
CDKL1	ENST00000216378.2 link	c.126C>A	p.Asp42Glu	missense_variant	Exon 2 of 9	1		ENSP00000216378.2	Q00532-3A0A5H1ZRP5
CDKL1	ENST00000356146.5 link	n.693C>A		non_coding_transcript_exon_variant	Exon 5 of 20	1
CDKL1	ENST00000531052.1 link	n.331C>A		non_coding_transcript_exon_variant	Exon 1 of 3	3

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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

GnomAD3 exomes

AF:

0.00000795

AC:

AN:

251422

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135898

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS 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:

0.00000342

AC:

AN:

1461546

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727100

show subpopulations

Gnomad4 AFR exome

AF:

0.000149

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152212

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74348

show subpopulations

Gnomad4 AFR

AF:

0.000145

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000189

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 03, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.126C>A (p.D42E) alteration is located in exon 1 (coding exon 1) of the CDKL1 gene. This alteration results from a C to A substitution at nucleotide position 126, causing the aspartic acid (D) at amino acid position 42 to be replaced by a glutamic acid (E). 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

Pathogenic

0.60

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.32

CADD

Benign

DANN

Benign

0.97

Eigen

Benign

-0.45

Eigen_PC

Benign

-0.52

FATHMM_MKL

Uncertain

0.86

M_CAP

Benign

0.016

MetaRNN

Benign

0.12

T;T

MetaSVM

Benign

-0.94

PrimateAI

Uncertain

0.53

PROVEAN

Uncertain

-3.9

D;D

REVEL

Benign

0.17

Sift

Uncertain

0.023

D;D

Sift4G

Uncertain

0.038

D;T

Vest4

0.46

MVP

0.048

MPC

0.30

ClinPred

0.33

GERP RS

0.45

gMVP

0.42

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