ENST00000379989.6:c.3003C>T

Variant names:

• chrX-18653454-C-T
• rs36022183
• ENST00000379989.6:c.3003C>T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BS2 BA1

This summary comes from the ClinGen Evidence Repository: The allele frequency of the p.His1001= variant in CDKL5 is 2.6% in Ashkenazi Jewish sub population in gnomAD, which is high enough to be classified as benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BA1). The p.His1001= variant is observed in at least 2 unaffected individuals (internal database) (BS2). In summary, the p.His1001= variant in CDKL5 is classified as benign based on the ACMG/AMP criteria (BA1, BS2). LINK:https://erepo.genome.network/evrepo/ui/classification/CA147631/MONDO:0100039/016

• Frequency:
  • Genomes: 𝑓 0.0034 (2 hom., 111 hem., cov: 23)
  • Exomes 𝑓: 0.0045 (19 hom. 1577 hem.)
• Consequence: CDKL5 ENST00000379989.6 synonymous
• Clinical Significance: Benign reviewed by expert panel U:1 B:13
• Conservation: PhyloP100: -0.0460

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]

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BS2: For more information check the summary or visit ClinGen Evidence Repository.
• BA1: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RS1	NM_000330.4	c.184+3199G>A		intron_variant	Intron 3 of 5	ENST00000379984.4	NP_000321.1
CDKL5	NM_001037343.2	c.3003C>T	p.His1001His	synonymous_variant	Exon 22 of 22		NP_001032420.1
CDKL5	NM_003159.3	c.3003C>T	p.His1001His	synonymous_variant	Exon 21 of 21		NP_003150.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDKL5	ENST00000379989.6	c.3003C>T	p.His1001His	synonymous_variant	Exon 22 of 22	1		ENSP00000369325.3
CDKL5	ENST00000379996.7	c.3003C>T	p.His1001His	synonymous_variant	Exon 21 of 21	1		ENSP00000369332.3
RS1	ENST00000379984.4	c.184+3199G>A		intron_variant	Intron 3 of 5	1	NM_000330.4	ENSP00000369320.3
CDKL5	ENST00000673617.1	n.275C>T		non_coding_transcript_exon_variant	Exon 3 of 3

Frequencies

GnomAD3 genomes AF: 0.00347 AC: 387 AN: 111572 Hom.: 2 Cov.: 23 AF XY: 0.00332 AC XY: 112 AN XY: 33766

Gnomad AFR AF: 0.000686

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00114

Gnomad ASJ AF: 0.0287

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00335

Gnomad FIN AF: 0.00383

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.00438

Gnomad OTH AF: 0.00470

GnomAD3 exomes AF: 0.00421 AC: 769 AN: 182476 Hom.: 5 AF XY: 0.00411 AC XY: 275 AN XY: 66976

Gnomad AFR exome AF: 0.000840

Gnomad AMR exome AF: 0.00201

Gnomad ASJ exome AF: 0.0258

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00121

Gnomad FIN exome AF: 0.00303

Gnomad NFE exome AF: 0.00506

Gnomad OTH exome AF: 0.00598

GnomAD4 exome AF: 0.00452 AC: 4958 AN: 1097832 Hom.: 19 Cov.: 31 AF XY: 0.00434 AC XY: 1577 AN XY: 363212

Gnomad4 AFR exome AF: 0.000985

Gnomad4 AMR exome AF: 0.00202

Gnomad4 ASJ exome AF: 0.0268

Gnomad4 EAS exome AF: 0.0000331

Gnomad4 SAS exome AF: 0.00148

Gnomad4 FIN exome AF: 0.00378

Gnomad4 NFE exome AF: 0.00455

Gnomad4 OTH exome AF: 0.00536

GnomAD4 genome AF: 0.00345 AC: 385 AN: 111626 Hom.: 2 Cov.: 23 AF XY: 0.00328 AC XY: 111 AN XY: 33830

Gnomad4 AFR AF: 0.000684

Gnomad4 AMR AF: 0.00114

Gnomad4 ASJ AF: 0.0287

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00336

Gnomad4 FIN AF: 0.00383

Gnomad4 NFE AF: 0.00435

Gnomad4 OTH AF: 0.00464

Alfa AF: 0.00630 Hom.: 50

Bravo AF: 0.00333

EpiCase AF: 0.00649

EpiControl AF: 0.00553

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:13

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:6

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 15, 2014

RettBASE

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: curation

Silent mutation, often found in cis with c.145+17A>G and c.3084G>A (p.T1028T) -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 15, 2012

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 10, 2012

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Developmental and epileptic encephalopathy, 2 Benign:2

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 16, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

CDKL5 disorder Benign:2

Aug 25, 2022

ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel

Significance: Benign

Review Status: reviewed by expert panel

Collection Method: curation

The allele frequency of the p.His1001= variant in CDKL5 is 2.6% in Ashkenazi Jewish sub population in gnomAD, which is high enough to be classified as benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BA1). The p.His1001= variant is observed in at least 2 unaffected individuals (internal database) (BS2). In summary, the p.His1001= variant in CDKL5 is classified as benign based on the ACMG/AMP criteria (BA1, BS2). -

Sep 20, 2024

Centre for Population Genomics, CPG

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

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 benign. At least the following criteria are met: The allele frequency of this variant in at least one population in gnomAD is higher than the 0.03% threshold defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like Disorders VCEP 3.0 (BA1). -

not provided Uncertain:1

Jun 01, 2016

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

CDKL5-related disorder Benign:1

Apr 03, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

History of neurodevelopmental disorder Benign:1

Jul 27, 2016

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Developmental and epileptic encephalopathy, 2;CN128785:Angelman syndrome-like Benign:1

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.25
DANN	Benign	0.59

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

Other links and lift over

dbSNP: rs36022183; hg19: chrX-18671574;