Genetic Variant CDKL5:c.-163+16813_-163+16817dupTTTTG (chrX-18442467-T-TTTTTG) – 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+16817dupTTTTG variant causes a intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.078 ( 380 hom., 1461 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

Benign criteria provided, single submitter B:1

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 -10 ACMG points.

BP6

Variant X-18442467-T-TTTTTG is Benign according to our data. Variant chrX-18442467-T-TTTTTG is described in ClinVar as [Benign]. Clinvar id is 1258365.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0938 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+16817dupTTTTG	intron_variant	Intron 1 of 17	ENST00000623535.2	NP_001310218.1	O76039-2
CDKL5	NM_001037343.2 link	c.-163+85_-163+89dupTTTTG	intron_variant	Intron 2 of 21		NP_001032420.1	O76039-1
CDKL5	NM_003159.3 link	c.-163+16813_-163+16817dupTTTTG	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+16773insTTTTG		intron_variant	Intron 1 of 17	1	NM_001323289.2	ENSP00000485244.1		O76039-2

Frequencies

GnomAD3 genomes

AF:

0.0785

AC:

8430

AN:

107365

Hom.:

381

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0968

Gnomad AMI

AF:

0.130

Gnomad AMR

AF:

0.0469

Gnomad ASJ

AF:

0.128

Gnomad EAS

AF:

0.0470

Gnomad SAS

AF:

0.0348

Gnomad FIN

AF:

0.0514

Gnomad MID

AF:

0.0885

Gnomad NFE

AF:

0.0781

Gnomad OTH

AF:

0.0908

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

222

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

102

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:

0.0785

AC:

8430

AN:

107412

Hom.:

380

Cov.:

AF XY:

0.0475

AC XY:

1461

AN XY:

30728

show subpopulations

African (AFR)

AF:

0.0968

AC:

2819

AN:

29128

American (AMR)

AF:

0.0466

AC:

471

AN:

10108

Ashkenazi Jewish (ASJ)

AF:

0.128

AC:

328

AN:

2559

East Asian (EAS)

AF:

0.0472

AC:

161

AN:

3414

South Asian (SAS)

AF:

0.0333

AC:

AN:

2491

European-Finnish (FIN)

AF:

0.0514

AC:

290

AN:

5637

Middle Eastern (MID)

AF:

0.0976

AC:

AN:

205

European-Non Finnish (NFE)

AF:

0.0781

AC:

4042

AN:

51764

Other (OTH)

AF:

0.0903

AC:

131

AN:

1450

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.516

Heterozygous variant carriers

286

571

857

1142

1428

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0304

Hom.:

111

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Jan 16, 2020

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

0.0

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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X-18442467-T-TTTTTG

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