rs587783158

Variant summary

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

The NM_001323289.2(CDKL5):​c.2596C>G​(p.Gln866Glu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 22)

Consequence

CDKL5
NM_001323289.2 missense

Scores

1
3
13

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.19
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]

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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=0.14655936).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CDKL5NM_001323289.2 linkc.2596C>G p.Gln866Glu missense_variant Exon 18 of 18 ENST00000623535.2 NP_001310218.1 O76039-2
CDKL5NM_001037343.2 linkc.2596C>G p.Gln866Glu missense_variant Exon 19 of 22 NP_001032420.1 O76039-1
CDKL5NM_003159.3 linkc.2596C>G p.Gln866Glu missense_variant Exon 18 of 21 NP_003150.1 O76039-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CDKL5ENST00000623535.2 linkc.2596C>G p.Gln866Glu missense_variant Exon 18 of 18 1 NM_001323289.2 ENSP00000485244.1 O76039-2
CDKL5ENST00000379989.6 linkc.2596C>G p.Gln866Glu missense_variant Exon 19 of 22 1 ENSP00000369325.3 O76039-1
CDKL5ENST00000379996.7 linkc.2596C>G p.Gln866Glu missense_variant Exon 18 of 21 1 ENSP00000369332.3 O76039-1
CDKL5ENST00000674046.1 linkc.2719C>G p.Gln907Glu missense_variant Exon 19 of 19 ENSP00000501174.1 A0A669KBC2

Frequencies

GnomAD3 genomes
Cov.:
22
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
22

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Feb 19, 2024
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Variant summary: CDKL5 c.2596C>G (p.Gln866Glu) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 183492 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.2596C>G in individuals affected with Early Infantile Epileptic Encephalopathy 2 and no experimental evidence demonstrating its impact on protein function have been reported. No submitters have cited clinical-significance assessments for this variant to ClinVar. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.11
BayesDel_addAF
Benign
-0.18
T
BayesDel_noAF
Benign
-0.50
CADD
Benign
18
DANN
Uncertain
0.98
DEOGEN2
Benign
0.023
T;T;.
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Benign
0.85
.;T;T
M_CAP
Uncertain
0.18
D
MetaRNN
Benign
0.15
T;T;T
MetaSVM
Benign
-0.69
T
MutationAssessor
Benign
1.1
L;L;L
PrimateAI
Uncertain
0.51
T
PROVEAN
Benign
-0.58
N;N;.
REVEL
Benign
0.10
Sift
Benign
0.068
T;T;.
Sift4G
Benign
0.096
T;T;T
Polyphen
0.19
B;B;.
Vest4
0.17
MutPred
0.13
Gain of helix (P = 0.0854);Gain of helix (P = 0.0854);Gain of helix (P = 0.0854);
MVP
0.68
MPC
0.39
ClinPred
0.54
D
GERP RS
5.7
Varity_R
0.24
gMVP
0.12

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-18646590; API