chrX-18604306-A-G

Position:

chrX-18604306-A-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_001323289.2(CDKL5):c.1382A>G(p.Asn461Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000992 in 1,209,668 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0000089 ( 0 hom., 0 hem., cov: 23)

Exomes 𝑓: 0.000010 ( 0 hom. 3 hem. )

Consequence

CDKL5
NM_001323289.2 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 2.04

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 -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.023553222).

BP6

Variant X-18604306-A-G is Benign according to our data. Variant chrX-18604306-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 143776.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Hemizygotes in GnomAdExome4 at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
CDKL5	NM_001323289.2 linkuse as main transcript	c.1382A>G	p.Asn461Ser	missense_variant	12/18	ENST00000623535.2	NP_001310218.1
CDKL5	NM_001037343.2 linkuse as main transcript	c.1382A>G	p.Asn461Ser	missense_variant	13/22		NP_001032420.1
CDKL5	NM_003159.3 linkuse as main transcript	c.1382A>G	p.Asn461Ser	missense_variant	12/21		NP_003150.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDKL5	ENST00000623535.2 linkuse as main transcript	c.1382A>G	p.Asn461Ser	missense_variant	12/18	1	NM_001323289.2	ENSP00000485244	P1	O76039-2

Frequencies

GnomAD3 genomes

AF:

0.00000893

AC:

AN:

111961

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34129

show subpopulations

Gnomad AFR

AF:

0.0000325

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000219

AC:

AN:

182865

Hom.:

AF XY:

0.0000296

AC XY:

AN XY:

67513

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000722

Gnomad SAS exome

AF:

0.000157

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000100

AC:

AN:

1097707

Hom.:

Cov.:

AF XY:

0.00000826

AC XY:

AN XY:

363113

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000331

Gnomad4 SAS exome

AF:

0.000129

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000119

Gnomad4 OTH exome

AF:

0.0000434

GnomAD4 genome

AF:

0.00000893

AC:

AN:

111961

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34129

show subpopulations

Gnomad4 AFR

AF:

0.0000325

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ExAC

AF:

0.0000412

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Likely benign, no assertion criteria provided

curation

RettBASE

May 09, 2014

In silico predictions: SIFT = tolerated, MutationTaster = polymorphism, PolyPhen2 = benign, AlignGVGD = benign (C0) -

CDKL5 disorder

Benign:1

Likely benign, criteria provided, single submitter

curation

Centre for Population Genomics, CPG

Jul 04, 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: The allele frequency of this variant in at least one population in gnomAD v4 is between 0.008% and 0.03% (BS1) Computational prediction analysis tools suggest no impact on gene product (REVEL score <= 0.15) (BP4). -

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

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 10, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.047

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.83

CADD

Benign

8.4

DANN

Benign

0.66

DEOGEN2

Benign

0.018

T;T;.;T;.;.

FATHMM_MKL

Benign

0.25

LIST_S2

Benign

0.81

.;T;T;T;T;T

M_CAP

Benign

0.028

MetaRNN

Benign

0.024

T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-1.1

N;.;.;N;.;N

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.30

PROVEAN

Benign

-0.38

N;.;.;N;.;.

REVEL

Benign

0.13

Sift

Benign

0.58

T;.;.;T;.;.

Sift4G

Benign

0.69

T;.;.;T;T;T

Polyphen

0.0

B;.;.;B;.;.

Vest4

0.083

MutPred

0.12

Gain of phosphorylation at N461 (P = 0.023);Gain of phosphorylation at N461 (P = 0.023);Gain of phosphorylation at N461 (P = 0.023);Gain of phosphorylation at N461 (P = 0.023);Gain of phosphorylation at N461 (P = 0.023);Gain of phosphorylation at N461 (P = 0.023);

MVP

0.47

MPC

0.27

ClinPred

0.0065

GERP RS

3.0

Varity_R

0.029

gMVP

0.035

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