rs1279388510

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_ModerateBS1_SupportingBS2

The NM_001323289.2(CDKL5):c.1094G>A(p.Ser365Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00000331 in 1,209,363 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S365T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 2 hem., cov: 23)

Exomes 𝑓: 0.0000018 ( 0 hom. 0 hem. )

Consequence

CDKL5
NM_001323289.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 3.77

Publications

1 publications found

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 Gene-Disease associations (from GenCC):

CDKL5 disorder
Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
developmental and epileptic encephalopathy, 2
Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
atypical Rett syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
genetic developmental and epileptic encephalopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
infantile spasms
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
precocious puberty
Inheritance: XL Classification: LIMITED Submitted by: Ambry Genetics

CDKL5 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.19826627).

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000018 (2/111161) while in subpopulation SAS AF = 0.000769 (2/2600). AF 95% confidence interval is 0.000136. There are 0 homozygotes in GnomAd4. There are 2 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Hemizygotes in GnomAd4 at 2 XL,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDKL5	NM_001323289.2 link	c.1094G>A	p.Ser365Asn	missense_variant	Exon 12 of 18	ENST00000623535.2	NP_001310218.1	O76039-2
CDKL5	NM_001037343.2 link	c.1094G>A	p.Ser365Asn	missense_variant	Exon 13 of 22		NP_001032420.1	O76039-1
CDKL5	NM_003159.3 link	c.1094G>A	p.Ser365Asn	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.1094G>A	p.Ser365Asn	missense_variant	Exon 12 of 18	1	NM_001323289.2	ENSP00000485244.1		O76039-2

Frequencies

GnomAD3 genomes

AF:

0.0000180

AC:

AN:

111109

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000767

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000109

AC:

AN:

183462

AF XY:

0.00

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000244

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000182

AC:

AN:

1098202

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

363556

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26402

American (AMR)

AF:

0.00

AC:

AN:

35207

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19385

East Asian (EAS)

AF:

0.00

AC:

AN:

30206

South Asian (SAS)

AF:

0.00

AC:

AN:

54148

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40533

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4137

European-Non Finnish (NFE)

AF:

0.00000238

AC:

AN:

842089

Other (OTH)

AF:

0.00

AC:

AN:

46095

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000180

AC:

AN:

111161

Hom.:

Cov.:

AF XY:

0.0000599

AC XY:

AN XY:

33401

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30545

American (AMR)

AF:

0.00

AC:

AN:

10421

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2639

East Asian (EAS)

AF:

0.00

AC:

AN:

3516

South Asian (SAS)

AF:

0.000769

AC:

AN:

2600

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5963

Middle Eastern (MID)

AF:

0.00

AC:

AN:

215

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53060

Other (OTH)

AF:

0.00

AC:

AN:

1514

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Nov 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

CDKL5: PM2 -

Developmental and epileptic encephalopathy, 2;CN128785:Angelman syndrome-like

Uncertain:1

Dec 11, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 365 of the CDKL5 protein (p.Ser365Asn). This variant is present in population databases (no rsID available, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with CDKL5-related conditions. ClinVar contains an entry for this variant (Variation ID: 1503908). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CDKL5 protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.44

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.041

T;T;.;T;.;.

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.91

.;D;D;D;D;D

M_CAP

Pathogenic

0.59

MetaRNN

Benign

0.20

T;T;T;T;T;T

MetaSVM

Benign

-0.45

MutationAssessor

Benign

1.2

L;.;.;L;.;L

PhyloP100

3.8

PrimateAI

Uncertain

0.64

PROVEAN

Benign

-0.85

N;.;.;N;.;.

REVEL

Benign

0.085

Sift

Uncertain

0.0010

D;.;.;D;.;.

Sift4G

Benign

0.073

T;.;.;T;T;T

Polyphen

0.88

P;.;.;P;.;.

Vest4

0.19

MutPred

0.21

Loss of glycosylation at S365 (P = 0.2269);Loss of glycosylation at S365 (P = 0.2269);Loss of glycosylation at S365 (P = 0.2269);Loss of glycosylation at S365 (P = 0.2269);Loss of glycosylation at S365 (P = 0.2269);Loss of glycosylation at S365 (P = 0.2269);

MVP

0.77

MPC

0.44

ClinPred

0.34

GERP RS

5.2

Varity_R

0.62

gMVP

0.53

Mutation Taster

=92/8

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over