rs777401314

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001323289.2(CDKL5):​c.-440G>T variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000477 in 113,114 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 21 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00048 ( 0 hom., 21 hem., cov: 24)

Consequence

CDKL5
NM_001323289.2 upstream_gene

Scores

2

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1B:2

Conservation

PhyloP100: 1.92
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 Benign. Variant got -20 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.74).
BP6
Variant X-18425418-G-T is Benign according to our data. Variant chrX-18425418-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 189604.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS1
Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000477 (54/113114) while in subpopulation SAS AF= 0.00181 (5/2770). AF 95% confidence interval is 0.000711. There are 0 homozygotes in gnomad4. There are 21 alleles in male gnomad4 subpopulation. Median coverage is 24. This position pass quality control queck.
BS2
High Hemizygotes in GnomAd4 at 21 XL gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CDKL5NM_001323289.2 linkc.-440G>T upstream_gene_variant ENST00000623535.2 NP_001310218.1 O76039-2
CDKL5NM_003159.3 linkc.-440G>T upstream_gene_variant NP_003150.1 O76039-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CDKL5ENST00000623535.2 linkc.-440G>T upstream_gene_variant 1 NM_001323289.2 ENSP00000485244.1 O76039-2
CDKL5ENST00000379996.7 linkc.-440G>T upstream_gene_variant 1 ENSP00000369332.3 O76039-1
CDKL5ENST00000674046.1 linkc.-440G>T upstream_gene_variant ENSP00000501174.1 A0A669KBC2

Frequencies

GnomAD3 genomes
AF:
0.000486
AC:
55
AN:
113064
Hom.:
0
Cov.:
24
AF XY:
0.000625
AC XY:
22
AN XY:
35200
show subpopulations
Gnomad AFR
AF:
0.0000963
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00216
Gnomad FIN
AF:
0.000796
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000731
Gnomad OTH
AF:
0.00130
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome
AF:
0.000477
AC:
54
AN:
113114
Hom.:
0
Cov.:
24
AF XY:
0.000596
AC XY:
21
AN XY:
35260
show subpopulations
Gnomad4 AFR
AF:
0.0000961
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00181
Gnomad4 FIN
AF:
0.000796
Gnomad4 NFE
AF:
0.000731
Gnomad4 OTH
AF:
0.00129
Alfa
AF:
0.000648
Hom.:
2
Bravo
AF:
0.000529

ClinVar

Significance: Benign/Likely benign
Submissions summary: Uncertain:1Benign:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Atypical Rett syndrome Uncertain:1
Mar 13, 2014
RettBASE
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: curation

No parental testing, unreported SNP -

CDKL5 disorder Benign:1
Jun 28, 2024
Centre for Population Genomics, CPG
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: curation

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 benign. At least the following criteria are met: The allele frequency of this variant in at least one population in gnomAD v3 is higher than the 0.03% threshold defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like Disorders VCEP 3.0 (BA1). -

not provided Benign:1
Mar 01, 2023
CeGaT Center for Human Genetics Tuebingen
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

CDKL5: BS2 -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.74
CADD
Benign
16
DANN
Benign
0.83

Splicing

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.

Other links and lift over

dbSNP: rs777401314; hg19: chrX-18443538; API