rs866859766

Positions:

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2

The NM_003159.3(CDKL5):c.2980G>A(p.Gly994Arg) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000164 in 1,097,473 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely benign (★★★).

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 0.000016 ( 0 hom. 3 hem. )

Consequence

CDKL5
NM_003159.3 missense, splice_region

Scores

Splicing: ADA: 0.9860

Clinical Significance

Likely benign reviewed by expert panel U:1B:2

Conservation

PhyloP100: 0.00600

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 links:

RS1 (HGNC:10457): (retinoschisin 1) This gene encodes an extracellular protein that plays a crucial role in the cellular organization of the retina. The encoded protein is assembled and secreted from photoreceptors and bipolar cells as a homo-oligomeric protein complex. Mutations in this gene are responsible for X-linked retinoschisis, a common, early-onset macular degeneration in males that results in a splitting of the inner layers of the retina and severe loss in vision. [provided by RefSeq, Oct 2008]

RS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP6

Variant X-18650592-G-A is Benign according to our data. Variant chrX-18650592-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 375543.Status of the report is reviewed_by_expert_panel, 3 stars.

BS1

Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.0000164 (18/1097473) while in subpopulation SAS AF= 0.000111 (6/54135). AF 95% confidence interval is 0.0000477. There are 0 homozygotes in gnomad4_exome. There are 3 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck.

BS2

High Hemizygotes in GnomAdExome4 at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RS1	NM_000330.4 link	c.185-3260C>T		intron_variant		ENST00000379984.4	NP_000321.1	O15537

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
CDKL5	ENST00000379989.6 link	c.2980G>A	p.Gly994Arg	missense_variant, splice_region_variant	21/22	1		ENSP00000369325.3	O76039-1
CDKL5	ENST00000379996.7 link	c.2980G>A	p.Gly994Arg	missense_variant, splice_region_variant	20/21	1		ENSP00000369332.3	O76039-1
RS1	ENST00000379984.4 link	c.185-3260C>T		intron_variant		1	NM_000330.4	ENSP00000369320.3	O15537
CDKL5	ENST00000673617.1 link	n.252G>A		splice_region_variant, non_coding_transcript_exon_variant	2/3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000547

AC:

AN:

182807

Hom.:

AF XY:

0.0000149

AC XY:

AN XY:

67319

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000123

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000164

AC:

AN:

1097473

Hom.:

Cov.:

AF XY:

0.00000827

AC XY:

AN XY:

362841

show subpopulations

Gnomad4 AFR exome

AF:

0.0000379

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000331

Gnomad4 SAS exome

AF:

0.000111

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000119

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000264

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:1Benign:2

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Epileptic encephalopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Neurogenetics Laboratory - MEYER, AOU Meyer

Nov 16, 2016

- -

CDKL5 disorder

Benign:1

Likely benign, reviewed by expert panel

curation

ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel

Feb 20, 2023

RS1(NM_000330.4) and an alternative transcript of CDKL5 (NM_003159.2) are overlapping transcripts; however, these variants are in the noncoding 3' region of the main CDKL5 transcript (NM_001323289.2). The c.2980G>A (p.Gly994Arg) variant in CDKL5 transcript (NM_003159.2) (RS1 c.185-3260C>T) is present in 0 female/1 male individual in gnomAD v2.1.1 (0.001227%) (not sufficient to meet BS1 criteria). Computational analysis prediction tools suggest that the p.Gly994Arg variant in CDKL5 does not have a deleterious impact; however this information does not predict clinical significance on its own (BP4). The p.Gly994Arg variant in CDKL5 is observed in at least 1 unaffected individual (PMID 29264392) (BS2_Supporting). In summary, the p.Gly994Arg in CDKL5 is classified as likely benign based on the ACMG/AMP criteria (BS2_Supporting, BP4). -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 18, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.59

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.025

T;T

FATHMM_MKL

Benign

0.020

LIST_S2

Benign

0.50

.;T

M_CAP

Pathogenic

0.70

MetaRNN

Benign

0.13

T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.0

N;N

PrimateAI

Benign

0.27

PROVEAN

Benign

-0.45

N;N

REVEL

Benign

0.086

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

0.0040

B;B

Vest4

0.35

MutPred

0.20

Gain of MoRF binding (P = 0.0199);Gain of MoRF binding (P = 0.0199);

MVP

0.25

MPC

1.2

ClinPred

0.32

GERP RS

-0.19

Varity_R

0.17

gMVP

0.046

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.99

dbscSNV1_RF

Pathogenic

0.87

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over