dbSNP rs748459878: CDKL5:p.Asn748Thr (chrX-18613242-A-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_ModerateBP6_Moderate

The NM_001323289.2(CDKL5):c.2243A>C(p.Asn748Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N748S) has been classified as Benign.

Frequency

Genomes: not found (cov: 22)

Consequence

CDKL5
NM_001323289.2 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 2.91

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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.25938752).

BP6

Variant X-18613242-A-C is Benign according to our data. Variant chrX-18613242-A-C is described in ClinVar as Likely_benign. ClinVar VariationId is 657569.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
CDKL5	NM_001323289.2 link	c.2243A>C	p.Asn748Thr	missense_variant	Exon 15 of 18	ENST00000623535.2	NP_001310218.1
CDKL5	NM_001037343.2 link	c.2243A>C	p.Asn748Thr	missense_variant	Exon 16 of 22		NP_001032420.1
CDKL5	NM_003159.3 link	c.2243A>C	p.Asn748Thr	missense_variant	Exon 15 of 21		NP_003150.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDKL5	ENST00000623535.2 link	c.2243A>C	p.Asn748Thr	missense_variant	Exon 15 of 18	1	NM_001323289.2	ENSP00000485244.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

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

Benign:1

Jun 10, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.41

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.053

T;T;T;.;.

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.95

.;D;D;D;D

M_CAP

Uncertain

0.20

MetaRNN

Benign

0.26

T;T;T;T;T

MetaSVM

Benign

-0.58

MutationAssessor

Benign

1.9

L;.;L;.;L

PhyloP100

2.9

PrimateAI

Uncertain

0.62

PROVEAN

Benign

-1.5

N;.;N;.;.

REVEL

Benign

0.28

Sift

Uncertain

0.0020

D;.;D;.;.

Sift4G

Benign

0.26

T;.;T;T;T

Polyphen

0.97

D;.;D;.;.

Vest4

0.39

MutPred

0.082

Gain of glycosylation at N748 (P = 0.0206);Gain of glycosylation at N748 (P = 0.0206);Gain of glycosylation at N748 (P = 0.0206);Gain of glycosylation at N748 (P = 0.0206);Gain of glycosylation at N748 (P = 0.0206);

MVP

0.82

MPC

0.62

ClinPred

0.86

GERP RS

5.0

Varity_R

0.57

gMVP

0.19

Mutation Taster

=74/26

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