dbSNP rs786204954: CDKL5:p.Gln770Lys (chrX-18619898-C-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_001323289.2(CDKL5):c.2308C>A(p.Gln770Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. Q770H) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 0.0 ( 0 hom. 0 hem. )

Failed GnomAD Quality Control

Consequence

CDKL5
NM_001323289.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1B:1

Conservation

PhyloP100: 4.42

Publications

0 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: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.28485432).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001323289.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CDKL5	NM_001323289.2	MANE Select	c.2308C>A	p.Gln770Lys	missense	Exon 16 of 18	NP_001310218.1	O76039-2
CDKL5	NM_001037343.2		c.2308C>A	p.Gln770Lys	missense	Exon 17 of 22	NP_001032420.1	O76039-1
CDKL5	NM_003159.3		c.2308C>A	p.Gln770Lys	missense	Exon 16 of 21	NP_003150.1	O76039-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CDKL5	ENST00000623535.2	TSL:1 MANE Select	c.2308C>A	p.Gln770Lys	missense	Exon 16 of 18	ENSP00000485244.1	O76039-2
CDKL5	ENST00000379989.6	TSL:1	c.2308C>A	p.Gln770Lys	missense	Exon 17 of 22	ENSP00000369325.3	O76039-1
CDKL5	ENST00000379996.7	TSL:1	c.2308C>A	p.Gln770Lys	missense	Exon 16 of 21	ENSP00000369332.3	O76039-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1084280

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

351372

African (AFR)

AF:

0.00

AC:

AN:

26146

American (AMR)

AF:

0.00

AC:

AN:

35029

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19238

East Asian (EAS)

AF:

0.00

AC:

AN:

30070

South Asian (SAS)

AF:

0.00

AC:

AN:

53172

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40451

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4067

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

830472

Other (OTH)

AF:

0.00

AC:

AN:

45635

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

CDKL5 disorder (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.42

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.037

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.93

M_CAP

Pathogenic

0.69

MetaRNN

Benign

0.28

MetaSVM

Benign

-0.92

MutationAssessor

Benign

1.7

PhyloP100

4.4

PrimateAI

Uncertain

0.70

PROVEAN

Benign

-1.0

REVEL

Benign

0.092

Sift

Uncertain

0.022

Sift4G

Benign

0.081

Polyphen

0.43

Vest4

0.21

MutPred

0.11

Gain of ubiquitination at Q770 (P = 0.0117)

MVP

0.81

MPC

0.46

ClinPred

0.74

GERP RS

5.4

Varity_R

0.46

gMVP

0.23

Mutation Taster

=89/11

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over