Variant rs62643617 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001323289.2(CDKL5):c.2378T>C(p.Val793Ala) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00001 in 1,095,234 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 7 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 22)

Exomes 𝑓: 0.000010 ( 0 hom. 7 hem. )

Consequence

CDKL5
NM_001323289.2 missense, splice_region

Scores

Splicing: ADA: 0.09396

Clinical Significance

Uncertain significance criteria provided, single submitter U:2

Conservation

PhyloP100: 5.50

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 Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.23061052).

BS2

High Hemizygotes in GnomAdExome4 at 7 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDKL5	NM_001323289.2 linkuse as main transcript	c.2378T>C	p.Val793Ala	missense_variant, splice_region_variant	17/18	ENST00000623535.2	NP_001310218.1	O76039-2
CDKL5	NM_001037343.2 linkuse as main transcript	c.2378T>C	p.Val793Ala	missense_variant, splice_region_variant	18/22		NP_001032420.1	O76039-1
CDKL5	NM_003159.3 linkuse as main transcript	c.2378T>C	p.Val793Ala	missense_variant, splice_region_variant	17/21		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.2378T>C	p.Val793Ala	missense_variant, splice_region_variant	17/18	1	NM_001323289.2	ENSP00000485244.1		O76039-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000547

AC:

AN:

182886

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

67408

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000122

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000100

AC:

AN:

1095234

Hom.:

Cov.:

AF XY:

0.0000194

AC XY:

AN XY:

360830

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000131

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

not specified

Uncertain:1

Uncertain significance, no assertion criteria provided

curation

RettBASE

Mar 13, 2014

Not a conserved amino acid residue, sidechain effects likely to be conservative; no parental DNA available for testing; In silico prediction: SIFT = deleterious, MutationTaster = disease-causing, PolyPhen2 = possibly damaging, AlignGVGD = benign (C0) -

CDKL5 disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

curation

Centre for Population Genomics, CPG

Sep 16, 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.092

BayesDel_noAF

Benign

-0.37

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.042

T;T;T;.

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.75

.;T;T;T

M_CAP

Pathogenic

0.40

MetaRNN

Benign

0.23

T;T;T;T

MetaSVM

Benign

-0.37

MutationAssessor

Benign

1.5

L;.;L;L

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-0.95

N;.;N;.

REVEL

Benign

0.19

Sift

Uncertain

0.0020

D;.;D;.

Sift4G

Uncertain

0.0050

D;.;D;D

Polyphen

0.62

P;.;P;.

Vest4

0.27

MutPred

0.15

Loss of stability (P = 0.0313);Loss of stability (P = 0.0313);Loss of stability (P = 0.0313);Loss of stability (P = 0.0313);

MVP

0.77

MPC

0.42

ClinPred

0.31

GERP RS

6.0

Varity_R

0.26

gMVP

0.083

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.094

dbscSNV1_RF

Benign

0.26

SpliceAI score (max)

0.050

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