rs781427744

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP5BS1BS2

This summary comes from the ClinGen Evidence Repository: The allele frequency of the p.Leu522Val variant in CDKL5 is 0.011% in European Non-Finnish sub population in gnomAD, which is high enough to meet the BS1 criteria based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BS1). Additionally, the p.Leu522Val variant is observed in at least 2 unaffected individuals (internal database - GeneDx, internal database - Ambry Genetics) (BS2) and is found in a patient with an alternate molecular basis of disease (internal database - GeneDx) (BP5). In summary, the p.Leu522Val variant in CDKL5 is classified as Benign for CDKL5-associated disorder according to ACMG/AMP criteria (BS1, BS2, BP5). LINK:https://erepo.genome.network/evrepo/ui/classification/CA10360394/MONDO:0100039/016

Frequency

Genomes: 𝑓 0.000054 ( 0 hom., 2 hem., cov: 23)

Exomes 𝑓: 0.000025 ( 0 hom. 15 hem. )

Consequence

CDKL5
NM_001323289.2 missense

Scores

Clinical Significance

Benign reviewed by expert panel U:1B:4

Conservation

PhyloP100: 0.257

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: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet, G2P
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 -9 ACMG points.

BP5

For more information check the summary or visit ClinGen Evidence Repository.

BS1

For more information check the summary or visit ClinGen Evidence Repository.

BS2

For more information check the summary or visit ClinGen Evidence Repository.

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.1564T>G	p.Leu522Val	missense	Exon 12 of 18	NP_001310218.1	O76039-2
CDKL5	NM_001037343.2		c.1564T>G	p.Leu522Val	missense	Exon 13 of 22	NP_001032420.1	O76039-1
CDKL5	NM_003159.3		c.1564T>G	p.Leu522Val	missense	Exon 12 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.1564T>G	p.Leu522Val	missense	Exon 12 of 18	ENSP00000485244.1	O76039-2
CDKL5	ENST00000379989.6	TSL:1	c.1564T>G	p.Leu522Val	missense	Exon 13 of 22	ENSP00000369325.3	O76039-1
CDKL5	ENST00000379996.7	TSL:1	c.1564T>G	p.Leu522Val	missense	Exon 12 of 21	ENSP00000369332.3	O76039-1

Frequencies

GnomAD3 genomes

AF:

0.0000538

AC:

AN:

111544

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:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000113

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000109

AC:

AN:

183420

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:

0.0000246

AC:

AN:

1098189

Hom.:

Cov.:

AF XY:

0.0000413

AC XY:

AN XY:

363543

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:

19386

East Asian (EAS)

AF:

0.00

AC:

AN:

30206

South Asian (SAS)

AF:

0.00

AC:

AN:

54145

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40534

Middle Eastern (MID)

AF:

0.000242

AC:

AN:

4137

European-Non Finnish (NFE)

AF:

0.0000261

AC:

AN:

842077

Other (OTH)

AF:

0.0000868

AC:

AN:

46095

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000538

AC:

AN:

111544

Hom.:

Cov.:

AF XY:

0.0000593

AC XY:

AN XY:

33740

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30634

American (AMR)

AF:

0.00

AC:

AN:

10526

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2650

East Asian (EAS)

AF:

0.00

AC:

AN:

3559

South Asian (SAS)

AF:

0.00

AC:

AN:

2657

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6002

Middle Eastern (MID)

AF:

0.00

AC:

AN:

237

European-Non Finnish (NFE)

AF:

0.000113

AC:

AN:

53100

Other (OTH)

AF:

0.00

AC:

AN:

1498

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000174

Hom.:

Bravo

AF:

0.0000378

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

CDKL5 disorder (1)

Developmental and epileptic encephalopathy, 2;CN128785:Angelman syndrome-like (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.097

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.66

CADD

Benign

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.029

FATHMM_MKL

Uncertain

0.82

LIST_S2

Uncertain

0.90

M_CAP

Benign

0.042

MetaRNN

Benign

0.072

MetaSVM

Benign

-0.93

MutationAssessor

Benign

1.9

PhyloP100

0.26

PrimateAI

Uncertain

0.59

PROVEAN

Benign

-0.26

REVEL

Benign

0.20

Sift

Benign

0.038

Sift4G

Benign

0.10

Polyphen

0.012

Vest4

0.15

MutPred

0.064

Gain of glycosylation at S519 (P = 0.0906)

MVP

0.60

MPC

0.58

ClinPred

0.051

GERP RS

0.51

Varity_R

0.079

gMVP

0.25

Mutation Taster

=97/3

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over