Variant X-18604324-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4BP6_Very_Strong

The NM_001323289.2(CDKL5):c.1400A>G(p.His467Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000109 in 1,097,196 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 Likely benign (★★).

Frequency

Genomes: not found (cov: 22)

Exomes 𝑓: 0.000011 ( 0 hom. 1 hem. )

Consequence

CDKL5
NM_001323289.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 7.01

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 Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.40388528).

BP6

Variant X-18604324-A-G is Benign according to our data. Variant chrX-18604324-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 158178.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDKL5	NM_001323289.2 link	c.1400A>G	p.His467Arg	missense_variant	Exon 12 of 18	ENST00000623535.2	NP_001310218.1	O76039-2
CDKL5	NM_001037343.2 link	c.1400A>G	p.His467Arg	missense_variant	Exon 13 of 22		NP_001032420.1	O76039-1
CDKL5	NM_003159.3 link	c.1400A>G	p.His467Arg	missense_variant	Exon 12 of 21		NP_003150.1	O76039-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDKL5	ENST00000623535.2 link	c.1400A>G	p.His467Arg	missense_variant	Exon 12 of 18	1	NM_001323289.2	ENSP00000485244.1		O76039-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000548

AC:

AN:

182529

Hom.:

AF XY:

0.00

AC XY:

AN XY:

67267

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:

0.0000123

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000109

AC:

AN:

1097196

Hom.:

Cov.:

AF XY:

0.00000276

AC XY:

AN XY:

362654

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:

0.0000185

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000131

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Likely benign, no assertion criteria provided	curation	RettBASE	May 09, 2014	Likely benign variation, found in normal female carrier; reported as c.1399A>G, but should be c.1400A>G; in silico predictions: SIFT = deleterious, MutationTaster = disease-causing, PolyPhen2 = probably damaging, AlignGVGD = C25 -

Developmental and epileptic encephalopathy, 2

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Aug 28, 2019

A heterozygous missense variant, NM_003159.2(CDKL5):c.1400A>G, has been identified in exon 12 of 21 of the CDKL5 gene. The variant is predicted to result in a minor amino acid change from His to Arg at position 467 of the protein (NP_003150.1(CDKL5):p.(His467Arg)). The His residue at this position has high conservation (100 vertebrates, UCSC), but is not located within a well established functional domain. In-silico predictions for this variant are consistently pathogenic (Polyphen, SIFT, CADD, Mutation Taster). The variant is present in the gnomAD database at a frequency of 0.0005% (1 heterozyogte, 0 homozygotes, 0 hemizygoutes). The variant has been previously described as benign and segregated with disease in one family with disease (ClinVar, RettBASE, Evans et al 2005)). A different variant in the same codon resulting in a change to proline has also been reported as VUS (ClinVar, RettBASE, Liang et al 2011)). Based on the information available at the time of curation, this variant has been classified as LIKELY BENIGN. -

CDKL5 disorder

Benign:1

Likely benign, criteria provided, single submitter

curation

Centre for Population Genomics, CPG

Jul 01, 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 likely benign. At least the following criteria are met: This variant is present in 11 heterozygous and 1 hemizygous in gnomAD v4 . The variant is observed in at least 2 individuals with no features of CDKL5 disorder (BS2). PMID: 16015284 -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Apr 01, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.63

BayesDel_addAF

Pathogenic

0.20

BayesDel_noAF

Uncertain

0.040

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.20

T;T;.;T;.;.

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.87

.;D;D;D;D;D

M_CAP

Pathogenic

0.58

MetaRNN

Benign

0.40

T;T;T;T;T;T

MetaSVM

Uncertain

-0.13

MutationAssessor

Benign

1.9

M;.;.;M;.;M

PrimateAI

Uncertain

0.76

PROVEAN

Uncertain

-3.0

D;.;.;D;.;.

REVEL

Uncertain

0.40

Sift

Uncertain

0.0010

D;.;.;D;.;.

Sift4G

Benign

0.069

T;.;.;T;T;T

Polyphen

1.0

D;.;.;D;.;.

Vest4

0.72

MutPred

0.27

Gain of MoRF binding (P = 0.008);Gain of MoRF binding (P = 0.008);Gain of MoRF binding (P = 0.008);Gain of MoRF binding (P = 0.008);Gain of MoRF binding (P = 0.008);Gain of MoRF binding (P = 0.008);

MVP

0.88

MPC

0.57

ClinPred

0.45

GERP RS

6.1

Varity_R

0.73

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