Genetic Variant NM_001323289.2:c.-163+16793_-163+16817delTTTTGTTTTGTTTTGTTTTGTTTTG (chrX-18442467-TTTTTGTTTTGTTTTGTTTTGTTTTG-T) – 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+16793_-163+16817delTTTTGTTTTGTTTTGTTTTGTTTTG variant causes a intron change involving the alteration of a non-conserved nucleotide. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0042 ( 4 hom., 105 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: 0.942

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 afr. GnomAd4 allele frequency = 0.00423 (455/107482) while in subpopulation AFR AF = 0.0142 (414/29153). AF 95% confidence interval is 0.0131. There are 4 homozygotes in GnomAd4. There are 105 alleles in the male GnomAd4 subpopulation. Median coverage is 18. This position passed quality control check.

BS2

High AC in GnomAd4 at 455 XL,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
CDKL5	NM_001323289.2 link	c.-163+16793_-163+16817delTTTTGTTTTGTTTTGTTTTGTTTTG	intron_variant	Intron 1 of 17	ENST00000623535.2	NP_001310218.1	O76039-2
CDKL5	NM_001037343.2 link	c.-163+65_-163+89delTTTTGTTTTGTTTTGTTTTGTTTTG	intron_variant	Intron 2 of 21		NP_001032420.1	O76039-1
CDKL5	NM_003159.3 link	c.-163+16793_-163+16817delTTTTGTTTTGTTTTGTTTTGTTTTG	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+16773_-163+16797delTTTTGTTTTGTTTTGTTTTGTTTTG		intron_variant	Intron 1 of 17	1	NM_001323289.2	ENSP00000485244.1		O76039-2

Frequencies

GnomAD3 genomes

AF:

0.00424

AC:

455

AN:

107435

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0142

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00337

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:

0.0000193

Gnomad OTH

AF:

0.00419

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

223

Hom.:

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:

0.00423

AC:

455

AN:

107482

Hom.:

Cov.:

AF XY:

0.00341

AC XY:

105

AN XY:

30780

show subpopulations

African (AFR)

AF:

0.0142

AC:

414

AN:

29153

American (AMR)

AF:

0.00336

AC:

AN:

10113

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2560

East Asian (EAS)

AF:

0.00

AC:

AN:

3414

South Asian (SAS)

AF:

0.00

AC:

AN:

2491

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5646

Middle Eastern (MID)

AF:

0.00

AC:

AN:

205

European-Non Finnish (NFE)

AF:

0.0000193

AC:

AN:

51793

Other (OTH)

AF:

0.00414

AC:

AN:

1450

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

111

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.94

Mutation Taster

=100/0

polymorphism

(source)

Splicing

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

Publications

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NM_001323289.2:c.-163+16793_-163+16817delTTTTGTTTTGTTTTGTTTTGTTTTG

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