Genetic Variant NM_001323289.2:c.-163+16813_-163+16817delTTTTG (chrX-18442467-TTTTTG-T) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_ModerateBA1

The NM_001323289.2(CDKL5):c.-163+16813_-163+16817delTTTTG variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0449 in 107,666 control chromosomes in the GnomAD database, including 107 homozygotes. There are 924 hemizygotes in GnomAD. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.045 ( 107 hom., 923 hem., cov: 18)

Exomes 𝑓: 0.0045 ( 0 hom. 1 hem. )

Consequence

CDKL5
NM_001323289.2 intron

Scores

Not classified

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.566

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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP6

Variant X-18442467-TTTTTG-T is Benign according to our data. Variant chrX-18442467-TTTTTG-T is described in ClinVar as [Benign]. Clinvar id is 1234180.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.055 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
CDKL5	NM_001323289.2 link	c.-163+16813_-163+16817delTTTTG	intron_variant	Intron 1 of 17	ENST00000623535.2	NP_001310218.1	O76039-2
CDKL5	NM_001037343.2 link	c.-163+85_-163+89delTTTTG	intron_variant	Intron 2 of 21		NP_001032420.1	O76039-1
CDKL5	NM_003159.3 link	c.-163+16813_-163+16817delTTTTG	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+16777delTTTTG		intron_variant	Intron 1 of 17	1	NM_001323289.2	ENSP00000485244.1		O76039-2

Frequencies

GnomAD3 genomes

AF:

0.0450

AC:

4835

AN:

107399

Hom.:

107

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0332

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0214

Gnomad ASJ

AF:

0.0828

Gnomad EAS

AF:

0.0269

Gnomad SAS

AF:

0.0524

Gnomad FIN

AF:

0.0360

Gnomad MID

AF:

0.0619

Gnomad NFE

AF:

0.0567

Gnomad OTH

AF:

0.0454

GnomAD4 exome

AF:

0.00455

AC:

AN:

220

Hom.:

AF XY:

0.0100

AC XY:

AN XY:

100

show subpopulations

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:

0.00559

AC:

AN:

179

Other (OTH)

AF:

0.00

AC:

AN:

GnomAD4 genome

AF:

0.0450

AC:

4836

AN:

107446

Hom.:

107

Cov.:

AF XY:

0.0300

AC XY:

923

AN XY:

30762

show subpopulations

African (AFR)

AF:

0.0332

AC:

967

AN:

29153

American (AMR)

AF:

0.0214

AC:

216

AN:

10113

Ashkenazi Jewish (ASJ)

AF:

0.0828

AC:

212

AN:

2560

East Asian (EAS)

AF:

0.0272

AC:

AN:

3414

South Asian (SAS)

AF:

0.0526

AC:

131

AN:

2490

European-Finnish (FIN)

AF:

0.0360

AC:

203

AN:

5643

Middle Eastern (MID)

AF:

0.0683

AC:

AN:

205

European-Non Finnish (NFE)

AF:

0.0567

AC:

2935

AN:

51761

Other (OTH)

AF:

0.0448

AC:

AN:

1450

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

168

336

503

671

839

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0285

Hom.:

111

Bravo

AF:

0.0479

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Oct 08, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.57

Mutation Taster

=100/0

polymorphism (auto)

(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+16813_-163+16817delTTTTG

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over