Genetic Variant CDKL5:p.Asp797Asn (chrX-18625140-G-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001323289.2(CDKL5):c.2389G>A(p.Asp797Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0000706 in 1,204,742 control chromosomes in the GnomAD database, including 1 homozygotes. There are 20 hemizygotes in GnomAD. 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D797H) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., 1 hem., cov: 22)

Exomes 𝑓: 0.000073 ( 1 hom. 19 hem. )

Consequence

CDKL5
NM_001323289.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 6.89

Publications

6 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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.044061214).

BP6

Variant X-18625140-G-A is Benign according to our data. Variant chrX-18625140-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 189533.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. GnomAdExome4 allele frequency = 0.000073 (80/1095349) while in subpopulation AMR AF = 0.00151 (53/35199). AF 95% confidence interval is 0.00118. There are 1 homozygotes in GnomAdExome4. There are 19 alleles in the male GnomAdExome4 subpopulation. Median coverage is 29. This position passed quality control check.

BS2

High AC in GnomAd4 at 5 XL,AD gene.

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.2389G>A	p.Asp797Asn	missense	Exon 17 of 18	NP_001310218.1	O76039-2
CDKL5	NM_001037343.2		c.2389G>A	p.Asp797Asn	missense	Exon 18 of 22	NP_001032420.1	O76039-1
CDKL5	NM_003159.3		c.2389G>A	p.Asp797Asn	missense	Exon 17 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.2389G>A	p.Asp797Asn	missense	Exon 17 of 18	ENSP00000485244.1	O76039-2
CDKL5	ENST00000379989.6	TSL:1	c.2389G>A	p.Asp797Asn	missense	Exon 18 of 22	ENSP00000369325.3	O76039-1
CDKL5	ENST00000379996.7	TSL:1	c.2389G>A	p.Asp797Asn	missense	Exon 17 of 21	ENSP00000369332.3	O76039-1

Frequencies

GnomAD3 genomes

AF:

0.0000457

AC:

AN:

109344

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000985

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:

0.0000570

Gnomad OTH

AF:

0.000682

GnomAD2 exomes

AF:

0.000279

AC:

AN:

182916

AF XY:

0.000148

show subpopulations

Gnomad AFR exome

AF:

0.000152

Gnomad AMR exome

AF:

0.00146

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:

0.00155

GnomAD4 exome

AF:

0.0000730

AC:

AN:

1095349

Hom.:

Cov.:

AF XY:

0.0000526

AC XY:

AN XY:

360925

show subpopulations

African (AFR)

AF:

0.000114

AC:

AN:

26365

American (AMR)

AF:

0.00151

AC:

AN:

35199

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19368

East Asian (EAS)

AF:

0.00

AC:

AN:

30187

South Asian (SAS)

AF:

0.0000185

AC:

AN:

54088

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39854

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4132

European-Non Finnish (NFE)

AF:

0.0000202

AC:

AN:

840134

Other (OTH)

AF:

0.000130

AC:

AN:

46022

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:

0.0000457

AC:

AN:

109393

Hom.:

Cov.:

AF XY:

0.0000315

AC XY:

AN XY:

31757

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30062

American (AMR)

AF:

0.0000984

AC:

AN:

10167

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2631

East Asian (EAS)

AF:

0.00

AC:

AN:

3480

South Asian (SAS)

AF:

0.00

AC:

AN:

2418

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5633

Middle Eastern (MID)

AF:

0.00

AC:

AN:

218

European-Non Finnish (NFE)

AF:

0.0000570

AC:

AN:

52629

Other (OTH)

AF:

0.000674

AC:

AN:

1484

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

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:

0.00

Hom.:

Bravo

AF:

0.0000680

ExAC

AF:

0.000338

AC:

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (2)

CDKL5 disorder (1)

Developmental and epileptic encephalopathy, 2 (1)

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

Inborn genetic diseases (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.67

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.026

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.91

M_CAP

Pathogenic

0.66

MetaRNN

Benign

0.044

MetaSVM

Benign

-0.45

MutationAssessor

Benign

1.6

PhyloP100

6.9

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-0.73

REVEL

Benign

0.21

Sift

Benign

0.090

Sift4G

Uncertain

0.030

Polyphen

0.96

Vest4

0.23

MutPred

0.19

Gain of MoRF binding (P = 0.0487)

MVP

0.89

MPC

0.34

ClinPred

0.030

GERP RS

6.0

Varity_R

0.098

gMVP

0.12

Mutation Taster

=99/1

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.11

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