rs140332992

Positions:

• chrX-18510848-A-G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP7 BS2

This summary comes from the ClinGen Evidence Repository: The p.Arg31= variant in CDKL5 is present in 3 female and 2 male individuals in gnomAD (0.002%) (not sufficient to meet BS1 criteria). The p.Arg31= variant is observed in at least 2 unaffected individuals (internal database) (BS2). The silent p.Arg31= variant is not predicted to affect splicing using multiple computational tools and does not affect a highly conserved nucleotide (BP7). In summary, the p.Arg31= variant in CDKL5 is classified as likely benign based on the ACMG/AMP criteria (BS2, BP7). LINK:https://erepo.genome.network/evrepo/ui/classification/CA171658/MONDO:0100039/016

• Frequency:
  • Genomes: 𝑓 0.000045 (0 hom., 0 hem., cov: 23)
  • Exomes 𝑓: 0.000024 (0 hom. 9 hem.)
• Consequence: CDKL5 NM_001323289.2 synonymous
• Clinical Significance: Likely benign reviewed by expert panel U:2 B:5
• Conservation: PhyloP100: 0.862

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]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDKL5	NM_001323289.2	c.93A>G	p.Arg31=	synonymous_variant	3/18	ENST00000623535.2
CDKL5	NM_001037343.2	c.93A>G	p.Arg31=	synonymous_variant	4/22
CDKL5	NM_003159.3	c.93A>G	p.Arg31=	synonymous_variant	3/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDKL5	ENST00000623535.2	c.93A>G	p.Arg31=	synonymous_variant	3/18	1	NM_001323289.2	P1

Frequencies

GnomAD3 genomes AF: 0.0000448 AC: 5 AN: 111724 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 33898

Gnomad AFR AF: 0.0000975

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: 0.00424

Gnomad NFE AF: 0.0000188

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000219 AC: 4 AN: 182437 Hom.: 0 AF XY: 0.0000298 AC XY: 2 AN XY: 67039

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000365

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: 0.0000367

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000237 AC: 25 AN: 1057042 Hom.: 0 Cov.: 24 AF XY: 0.0000274 AC XY: 9 AN XY: 328494

Gnomad4 AFR exome AF: 0.000234

Gnomad4 AMR exome AF: 0.0000285

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: 0.0000199

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000447 AC: 5 AN: 111779 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 33963

Gnomad4 AFR AF: 0.0000973

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: 0.0000453

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:2 Benign:5

Revision: reviewed by expert panel

Submissions by phenotype

not provided Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 19, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2022	CDKL5: BP4, BP7 -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 10, 2015	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Aug 10, 2015

- -

CDKL5 disorder Benign:1

Likely benign, reviewed by expert panel

curation

ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel

Sep 01, 2022

The p.Arg31= variant in CDKL5 is present in 3 female and 2 male individuals in gnomAD (0.002%) (not sufficient to meet BS1 criteria). The p.Arg31= variant is observed in at least 2 unaffected individuals (internal database) (BS2). The silent p.Arg31= variant is not predicted to affect splicing using multiple computational tools and does not affect a highly conserved nucleotide (BP7). In summary, the p.Arg31= variant in CDKL5 is classified as likely benign based on the ACMG/AMP criteria (BS2, BP7). -

History of neurodevelopmental disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 16, 2017

In silico models in agreement (benign);Synonymous alterations with insufficient evidence to classify as benign -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 25, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	8.9
DANN	Benign	0.75

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs140332992; hg19: chrX-18528968;