X-18646060-C-T

Position:

chrX-18646060-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The ENST00000379989.6(CDKL5):c.2767C>T(p.Arg923Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000198 in 1,210,256 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 9 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R923H) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000045 ( 0 hom., 1 hem., cov: 22)

Exomes 𝑓: 0.000017 ( 0 hom. 8 hem. )

Consequence

CDKL5
ENST00000379989.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:2

Conservation

PhyloP100: -0.230

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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.02110511).

BP6

Variant X-18646060-C-T is Benign according to our data. Variant chrX-18646060-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 143810.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1, Benign=1}.

BS2

High Hemizygotes in GnomAdExome4 at 8 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
RS1	NM_000330.4 linkuse as main transcript	c.326+1131G>A		intron_variant		ENST00000379984.4	NP_000321.1
CDKL5	NM_001037343.2 linkuse as main transcript	c.2767C>T	p.Arg923Cys	missense_variant	20/22		NP_001032420.1
CDKL5	NM_003159.3 linkuse as main transcript	c.2767C>T	p.Arg923Cys	missense_variant	19/21		NP_003150.1
RS1	XM_047442337.1 linkuse as main transcript	c.230+1131G>A		intron_variant			XP_047298293.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDKL5	ENST00000379989.6 linkuse as main transcript	c.2767C>T	p.Arg923Cys	missense_variant	20/22	1		ENSP00000369325		O76039-1
CDKL5	ENST00000379996.7 linkuse as main transcript	c.2767C>T	p.Arg923Cys	missense_variant	19/21	1		ENSP00000369332		O76039-1
RS1	ENST00000379984.4 linkuse as main transcript	c.326+1131G>A		intron_variant		1	NM_000330.4	ENSP00000369320	P1
RS1	ENST00000476595.1 linkuse as main transcript	n.817+1131G>A		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes

AF:

0.0000446

AC:

AN:

112004

Hom.:

Cov.:

AF XY:

0.0000293

AC XY:

AN XY:

34174

show subpopulations

Gnomad AFR

AF:

0.0000650

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000372

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000188

Gnomad OTH

AF:

0.000671

GnomAD3 exomes

AF:

0.0000606

AC:

AN:

181639

Hom.:

AF XY:

0.0000890

AC XY:

AN XY:

67401

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000577

Gnomad SAS exome

AF:

0.000157

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000173

AC:

AN:

1098199

Hom.:

Cov.:

AF XY:

0.0000220

AC XY:

AN XY:

363555

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000166

Gnomad4 SAS exome

AF:

0.000148

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000594

Gnomad4 OTH exome

AF:

0.0000217

GnomAD4 genome

AF:

0.0000446

AC:

AN:

112057

Hom.:

Cov.:

AF XY:

0.0000292

AC XY:

AN XY:

34237

show subpopulations

Gnomad4 AFR

AF:

0.0000648

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000373

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000188

Gnomad4 OTH

AF:

0.000662

Bravo

AF:

0.0000340

ExAC

AF:

0.0000741

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, no assertion criteria provided

curation

RettBASE

Mar 13, 2014

Paper ambiguous as to carrier status; In silico prediction: SIFT = deleterious, MutationTaster = polymorphism, PolyPhen2 = benign, AlignGVGD = benign (C0) -

Developmental and epileptic encephalopathy, 2

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory of Inherited Metabolic Diseases, Research centre for medical genetics

Feb 14, 2020

- -

CDKL5 disorder

Benign:1

Likely benign, criteria provided, single submitter

curation

Centre for Population Genomics, CPG

Sep 19, 2024

This variant has been collected from RettBASE and curated to current modified ACMG/AMP criteria. Based on the classification scheme defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like Disorders Specifications to the ACMG/AMP Variant Interpretation Guidelines VCEP 3.0, this variant is classified as likely benign. At least the following criteria are met: The allele frequency of this variant in at least one population in gnomAD is between 0.008% and 0.03% (BS1). The variant is observed in at least 1 individual with no features of CDKL5 disorder (PMID: 19241098). Computational prediction analysis tools suggest no impact on gene product (REVEL score <= 0.15) (BP4). -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 30, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.50

CADD

Benign

5.0

DANN

Uncertain

0.99

DEOGEN2

Benign

0.051

T;T

FATHMM_MKL

Benign

0.0034

LIST_S2

Benign

0.56

.;T

M_CAP

Uncertain

0.20

MetaRNN

Benign

0.021

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

N;N

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.33

PROVEAN

Benign

-1.2

N;N

REVEL

Benign

0.13

Sift

Pathogenic

0.0

D;D

Sift4G

Uncertain

0.0070

D;D

Polyphen

0.34

B;B

Vest4

0.046

MutPred

0.12

Loss of MoRF binding (P = 0.0058);Loss of MoRF binding (P = 0.0058);

MVP

0.35

MPC

1.0

ClinPred

0.16

GERP RS

0.69

Varity_R

0.13

gMVP

0.32

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over