rs747554139

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001323289.2(CDKL5):c.2215C>G(p.Leu739Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000904 in 110,665 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. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. L739L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000090 ( 0 hom., 1 hem., cov: 22)

Exomes 𝑓: 9.2e-7 ( 0 hom. 1 hem. )

Failed GnomAD Quality Control

Consequence

CDKL5
NM_001323289.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0650

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: 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=0.045918316).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDKL5	NM_001323289.2 link	c.2215C>G	p.Leu739Val	missense_variant	Exon 15 of 18	ENST00000623535.2	NP_001310218.1	O76039-2
CDKL5	NM_001037343.2 link	c.2215C>G	p.Leu739Val	missense_variant	Exon 16 of 22		NP_001032420.1	O76039-1
CDKL5	NM_003159.3 link	c.2215C>G	p.Leu739Val	missense_variant	Exon 15 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.2215C>G	p.Leu739Val	missense_variant	Exon 15 of 18	1	NM_001323289.2	ENSP00000485244.1		O76039-2

Frequencies

GnomAD3 genomes

AF:

0.00000904

AC:

AN:

110628

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:

0.000384

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000545

AC:

AN:

183443

AF XY:

0.0000147

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

9.22e-7

AC:

AN:

1084991

Hom.:

Cov.:

AF XY:

0.00000284

AC XY:

AN XY:

352223

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26113

American (AMR)

AF:

0.00

AC:

AN:

34897

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19008

East Asian (EAS)

AF:

0.00

AC:

AN:

29493

South Asian (SAS)

AF:

0.0000186

AC:

AN:

53872

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39599

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4063

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

832576

Other (OTH)

AF:

0.00

AC:

AN:

45370

GnomAD4 genome

AF:

0.00000904

AC:

AN:

110665

Hom.:

Cov.:

AF XY:

0.0000304

AC XY:

AN XY:

32939

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30448

American (AMR)

AF:

0.00

AC:

AN:

10373

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2632

East Asian (EAS)

AF:

0.00

AC:

AN:

3540

South Asian (SAS)

AF:

0.000387

AC:

AN:

2587

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5722

Middle Eastern (MID)

AF:

0.00

AC:

AN:

214

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

52965

Other (OTH)

AF:

0.00

AC:

AN:

1499

ExAC

AF:

0.0000165

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.060

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.65

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.022

T;T;T;.;.

FATHMM_MKL

Benign

0.29

LIST_S2

Benign

0.78

.;T;T;T;T

M_CAP

Benign

0.050

MetaRNN

Benign

0.046

T;T;T;T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

1.1

L;.;L;.;L

PhyloP100

0.065

PrimateAI

Uncertain

0.66

PROVEAN

Benign

-0.34

N;.;N;.;.

REVEL

Benign

0.11

Sift

Benign

0.27

T;.;T;.;.

Sift4G

Benign

0.36

T;.;T;T;T

Polyphen

0.21

B;.;B;.;.

Vest4

0.13

MutPred

0.084

Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);

MVP

0.57

MPC

0.58

ClinPred

0.17

GERP RS

4.2

Varity_R

0.14

gMVP

0.13

Mutation Taster

=100/0

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

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

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over