Variant rs267608547 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_001323289.2(CDKL5):c.904C>T(p.Leu302Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000183 in 1,094,281 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 0.0000018 ( 0 hom. 1 hem. )

Consequence

CDKL5
NM_001323289.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:2

Conservation

PhyloP100: 7.38

Variant links:

Genes affected

CDKL5 (HGNC:11411): (cyclin dependent kinase like 5) This gene is a member of Ser/Thr protein kinase family and encodes a phosphorylated protein with protein kinase activity. Mutations in this gene have been associated with X-linked infantile spasm syndrome (ISSX), also known as X-linked West syndrome, and Rett syndrome (RTT). Alternate transcriptional splice variants have been characterized. [provided by RefSeq, Jul 2008]

CDKL5 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.42176068).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDKL5	NM_001323289.2 linkuse as main transcript	c.904C>T	p.Leu302Phe	missense_variant	11/18	ENST00000623535.2	NP_001310218.1	O76039-2
CDKL5	NM_001037343.2 linkuse as main transcript	c.904C>T	p.Leu302Phe	missense_variant	12/22		NP_001032420.1	O76039-1
CDKL5	NM_003159.3 linkuse as main transcript	c.904C>T	p.Leu302Phe	missense_variant	11/21		NP_003150.1	O76039-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDKL5	ENST00000623535.2 linkuse as main transcript	c.904C>T	p.Leu302Phe	missense_variant	11/18	1	NM_001323289.2	ENSP00000485244.1		O76039-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000545

AC:

AN:

183364

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

67850

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000722

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:

0.00000183

AC:

AN:

1094281

Hom.:

Cov.:

AF XY:

0.00000278

AC XY:

AN XY:

359787

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000663

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

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Developmental and epileptic encephalopathy, 2

Uncertain:1

Uncertain significance, no assertion criteria provided

curation

RettBASE

Mar 13, 2014

In silico prediction: SIFT = tolerated, MutationTaster = disease-causing, PolyPhen2 = probably damaging, AlignGVGD = benign (C0), no parental screening results -

CDKL5 disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

curation

Centre for Population Genomics, CPG

Sep 11, 2024

This variant has been collected from RettBASE and curated to current modified ACMG/AMP criteria. Based on the classification scheme defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like Disorders Specifications to the ACMG/AMP Variant Interpretation Guidelines VCEP 3.0, this variant is classified as a variant of uncertain significance. The allele frequency of this variant in one population in gnomAD is 0.006%, not meeting the criteria BS1. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Uncertain

0.059

BayesDel_noAF

Uncertain

0.040

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.045

T;T;.;T;.;.

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.94

.;D;D;D;D;D

M_CAP

Pathogenic

0.78

MetaRNN

Benign

0.42

T;T;T;T;T;T

MetaSVM

Benign

-0.54

MutationAssessor

Uncertain

2.1

M;.;.;M;.;M

PrimateAI

Uncertain

0.65

PROVEAN

Benign

-1.4

N;.;.;N;.;.

REVEL

Uncertain

0.31

Sift

Benign

0.21

T;.;.;T;.;.

Sift4G

Benign

0.40

T;.;.;T;T;T

Polyphen

0.99

D;.;.;D;.;.

Vest4

0.44

MutPred

0.34

Loss of catalytic residue at L302 (P = 0.0711);Loss of catalytic residue at L302 (P = 0.0711);Loss of catalytic residue at L302 (P = 0.0711);Loss of catalytic residue at L302 (P = 0.0711);Loss of catalytic residue at L302 (P = 0.0711);Loss of catalytic residue at L302 (P = 0.0711);

MVP

0.92

MPC

0.48

ClinPred

0.46

GERP RS

5.5

Varity_R

0.52

gMVP

0.41

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