Genetic Variant CDKL5:c.-163+16808_-163+16817dupTTTTGTTTTG (chrX-18442467-T-TTTTTGTTTTG) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1BS2

The NM_001323289.2(CDKL5):c.-163+16808_-163+16817dupTTTTGTTTTG variant causes a intron change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0035 ( 0 hom., 68 hem., cov: 18)

Exomes 𝑓: 0.0 ( 0 hom. 0 hem. )

Failed GnomAD Quality Control

Consequence

CDKL5
NM_001323289.2 intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.00

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: Benign. The variant received -8 ACMG points.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00352 (378/107486) while in subpopulation NFE AF = 0.00481 (249/51788). AF 95% confidence interval is 0.00432. There are 0 homozygotes in GnomAd4. There are 68 alleles in the male GnomAd4 subpopulation. Median coverage is 18. This position passed quality control check.

BS2

High AC in GnomAd4 at 378 XL,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
CDKL5	NM_001323289.2 link	c.-163+16808_-163+16817dupTTTTGTTTTG	intron_variant	Intron 1 of 17	ENST00000623535.2	NP_001310218.1	O76039-2
CDKL5	NM_001037343.2 link	c.-163+80_-163+89dupTTTTGTTTTG	intron_variant	Intron 2 of 21		NP_001032420.1	O76039-1
CDKL5	NM_003159.3 link	c.-163+16808_-163+16817dupTTTTGTTTTG	intron_variant	Intron 1 of 20		NP_003150.1	O76039-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDKL5	ENST00000623535.2 link	c.-163+16772_-163+16773insTTTTGTTTTG		intron_variant	Intron 1 of 17	1	NM_001323289.2	ENSP00000485244.1		O76039-2

Frequencies

GnomAD3 genomes

AF:

0.00350

AC:

376

AN:

107439

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00247

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00228

Gnomad ASJ

AF:

0.00352

Gnomad EAS

AF:

0.00204

Gnomad SAS

AF:

0.00120

Gnomad FIN

AF:

0.00177

Gnomad MID

AF:

0.00442

Gnomad NFE

AF:

0.00479

Gnomad OTH

AF:

0.00210

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

223

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

103

African (AFR)

AF:

0.00

AC:

AN:

American (AMR)

AF:

0.00

AC:

AN:

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

East Asian (EAS)

AF:

0.00

AC:

AN:

South Asian (SAS)

AF:

0.00

AC:

AN:

European-Finnish (FIN)

AF:

0.00

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

182

Other (OTH)

AF:

0.00

AC:

AN:

GnomAD4 genome

AF:

0.00352

AC:

378

AN:

107486

Hom.:

Cov.:

AF XY:

0.00221

AC XY:

AN XY:

30782

show subpopulations

African (AFR)

AF:

0.00250

AC:

AN:

29162

American (AMR)

AF:

0.00227

AC:

AN:

10113

Ashkenazi Jewish (ASJ)

AF:

0.00352

AC:

AN:

2560

East Asian (EAS)

AF:

0.00205

AC:

AN:

3414

South Asian (SAS)

AF:

0.00120

AC:

AN:

2491

European-Finnish (FIN)

AF:

0.00177

AC:

AN:

5646

Middle Eastern (MID)

AF:

0.00488

AC:

AN:

205

European-Non Finnish (NFE)

AF:

0.00481

AC:

249

AN:

51788

Other (OTH)

AF:

0.00207

AC:

AN:

1450

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.512

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00111

Hom.:

111

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.0

Mutation Taster

=100/0

polymorphism

(source)

Splicing

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.

X-18442467-TTTTTGTTTTGTTTTGTTTTGTTTTG-TTTTTGTTTTGTTTTGTTTTGTTTTGTTTTGTTTTG

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over