chrX-18650469-G-T

Position:

chrX-18650469-G-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP5BP4

This summary comes from the ClinGen Evidence Repository: 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.2857G>T (p.Ala953Ser) variant in CDKL5 transcript (NM_003159.2) (RS1 c.185-3137C>A) is present in 2 male individuals in gnomAD (0.002%) (not sufficient to meet BS1 criteria). The p.Ala953Ser variant is found in a patient with an alternate molecular basis of disease (internal database - Invitae) (BP5). Additionally, computational analysis prediction tools suggest that the p.Ala953Ser variant does not have a deleterious impact; however this information does not predict clinical significance on its own (BP4). In summary, the p.Ala953Ser variant in CDKL5 (NM_003159.2) is classified as likely benign based on the ACMG/AMP criteria (BP5, BP4). LINK:https://erepo.genome.network/evrepo/ui/classification/CA10360734/MONDO:0100039/034

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 0.000013 ( 0 hom. 7 hem. )

Consequence

CDKL5
ENST00000379989.6 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.799

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 Likely_benign. Variant got -2 ACMG points.

BP4

For more information check the summary or visit ClinGen Evidence Repository.

BP5

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
RS1	NM_000330.4 linkuse as main transcript	c.185-3137C>A		intron_variant		ENST00000379984.4	NP_000321.1
CDKL5	NM_001037343.2 linkuse as main transcript	c.2857G>T	p.Ala953Ser	missense_variant	21/22		NP_001032420.1
CDKL5	NM_003159.3 linkuse as main transcript	c.2857G>T	p.Ala953Ser	missense_variant	20/21		NP_003150.1
RS1	XM_047442337.1 linkuse as main transcript	c.-86C>A		5_prime_UTR_variant	1/4		XP_047298293.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RS1	ENST00000379984.4 linkuse as main transcript	c.185-3137C>A		intron_variant		1	NM_000330.4	ENSP00000369320	P1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000109

AC:

AN:

183508

Hom.:

AF XY:

0.0000294

AC XY:

AN XY:

67938

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:

0.0000244

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000127

AC:

AN:

1098130

Hom.:

Cov.:

AF XY:

0.0000193

AC XY:

AN XY:

363490

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:

0.0000166

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000237

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:1Benign:2

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Mar 14, 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.2857G>T (p.Ala953Ser) variant in CDKL5 transcript (NM_003159.2) (RS1 c.185-3137C>A) is present in 2 male individuals in gnomAD (0.002%) (not sufficient to meet BS1 criteria). The p.Ala953Ser variant is found in a patient with an alternate molecular basis of disease (internal database - Invitae) (BP5). Additionally, computational analysis prediction tools suggest that the p.Ala953Ser variant does not have a deleterious impact; however this information does not predict clinical significance on its own (BP4). In summary, the p.Ala953Ser variant in CDKL5 (NM_003159.2) is classified as likely benign based on the ACMG/AMP criteria (BP5, BP4). -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 14, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.71

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.025

T;T

FATHMM_MKL

Benign

0.082

LIST_S2

Benign

0.43

.;T

M_CAP

Uncertain

0.27

MetaRNN

Benign

0.090

T;T

MetaSVM

Benign

-0.91

MutationAssessor

Benign

0.0

N;N

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.24

PROVEAN

Benign

-0.59

N;N

REVEL

Benign

0.093

Sift

Uncertain

0.0080

D;D

Sift4G

Benign

0.61

T;T

Polyphen

0.018

B;B

Vest4

0.17

MutPred

0.21

Gain of phosphorylation at A953 (P = 0.0261);Gain of phosphorylation at A953 (P = 0.0261);

MVP

0.33

MPC

0.54

ClinPred

0.067

GERP RS

0.54

Varity_R

0.095

gMVP

0.025

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