Variant X-18653446-G-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_003159.3(CDKL5):c.2995G>T(p.Val999Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,209,217 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0000090 ( 0 hom., 0 hem., cov: 23)

Exomes 𝑓: 0.0000018 ( 0 hom. 1 hem. )

Consequence

CDKL5
NM_003159.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.515

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.09035358).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RS1	NM_000330.4 link	c.184+3207C>A		intron_variant		ENST00000379984.4	NP_000321.1	O15537
CDKL5	NM_001037343.2 link	c.2995G>T	p.Val999Leu	missense_variant	22/22		NP_001032420.1	O76039-1
CDKL5	NM_003159.3 link	c.2995G>T	p.Val999Leu	missense_variant	21/21		NP_003150.1	O76039-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
CDKL5	ENST00000379989.6 link	c.2995G>T	p.Val999Leu	missense_variant	22/22	1		ENSP00000369325.3	O76039-1
CDKL5	ENST00000379996.7 link	c.2995G>T	p.Val999Leu	missense_variant	21/21	1		ENSP00000369332.3	O76039-1
RS1	ENST00000379984.4 link	c.184+3207C>A		intron_variant		1	NM_000330.4	ENSP00000369320.3	O15537
CDKL5	ENST00000673617.1 link	n.267G>T		non_coding_transcript_exon_variant	3/3

Frequencies

GnomAD3 genomes

AF:

0.00000897

AC:

AN:

111490

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33678

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000188

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000550

AC:

AN:

181957

Hom.:

AF XY:

0.0000150

AC XY:

AN XY:

66519

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:

0.00000182

AC:

AN:

1097727

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

363133

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000238

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000897

AC:

AN:

111490

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33678

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000188

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ExAC

AF:

0.0000165

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.73

CADD

Benign

1.8

DANN

Benign

0.90

DEOGEN2

Benign

0.032

T;T

FATHMM_MKL

Benign

0.0076

LIST_S2

Benign

0.41

.;T

M_CAP

Pathogenic

0.41

MetaRNN

Benign

0.090

T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.0

N;N

PrimateAI

Benign

0.28

PROVEAN

Benign

-0.22

N;N

REVEL

Benign

0.10

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

0.0

B;B

Vest4

0.12

MutPred

0.23

Loss of sheet (P = 0.0142);Loss of sheet (P = 0.0142);

MVP

0.23

MPC

0.44

ClinPred

0.054

GERP RS

-0.0082

Varity_R

0.11

gMVP

0.028

Splicing

Name

Calibrated prediction

Score

Prediction

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over