X-18584261-A-G

Variant names:

• chrX-18584261-A-G
• rs267608480
• NM_001323289.2:c.464-2A>G

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1_Moderate PM2 PP5_Very_Strong

The NM_001323289.2(CDKL5):​c.464-2A>G variant causes a splice acceptor, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: CDKL5 NM_001323289.2 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3 O:1
• Conservation: PhyloP100: 9.32
• Publications: 3 publications found

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 Gene-Disease associations (from GenCC):

• CDKL5 disorder

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
• developmental and epileptic encephalopathy, 2

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• atypical Rett syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• genetic developmental and epileptic encephalopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• infantile spasms

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• precocious puberty

  Inheritance: XL Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.031564344 fraction of the gene. Cryptic splice site detected, with MaxEntScore 3.6, offset of 21, new splice context is: ttttgctcgtaatctgtcAGaag. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-18584261-A-G is Pathogenic according to our data. Variant chrX-18584261-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 156090.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDKL5	NM_001323289.2	c.464-2A>G		splice_acceptor_variant, intron_variant	Intron 7 of 17	ENST00000623535.2	NP_001310218.1
CDKL5	NM_001037343.2	c.464-2A>G		splice_acceptor_variant, intron_variant	Intron 8 of 21		NP_001032420.1
CDKL5	NM_003159.3	c.464-2A>G		splice_acceptor_variant, intron_variant	Intron 7 of 20		NP_003150.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDKL5	ENST00000623535.2	c.464-2A>G		splice_acceptor_variant, intron_variant	Intron 7 of 17	1	NM_001323289.2	ENSP00000485244.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1070373 Hom.: 0 Cov.: 26 AF XY: 0.00 AC XY: 0 AN XY: 339855

African (AFR) AF: 0.00 AC: 0 AN: 25849

American (AMR) AF: 0.00 AC: 0 AN: 35154

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19235

East Asian (EAS) AF: 0.00 AC: 0 AN: 30094

South Asian (SAS) AF: 0.00 AC: 0 AN: 53531

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40522

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4072

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 816732

Other (OTH) AF: 0.00 AC: 0 AN: 45184

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Developmental and epileptic encephalopathy, 2 Pathogenic:1

Mar 13, 2014

RettBASE

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: curation

Leads to exon 8 skipping, r.464_554del

Inborn genetic diseases Pathogenic:1

Feb 19, 2018

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.464-2A>G intronic pathogenic mutation results from an A to G substitution two nucleotides upstream from coding exon 7 in the CDKL5 gene. This mutation (denoted as IVS7-2A>G) was first described in an infant with microcephaly, severe developmental delay, failure to thrive, hand stereotypies, variable tone, and dysmorphic facial features, who met clinical criteria for Rett syndrome but whose features more closely resembled severe epileptic encephalopathy. Amplification of cDNA revealed 2 different RT-PCR products, and sequencing of the smaller product was consistent with loss of exon 8 (coding exon 7) (Evans JC et al. Eur. J. Hum. Genet., 2005 Oct;13:1113-20). This mutation has also been observed in an individual with early onset epileptic encephalopathy (Carvill GL et al. Nat. Genet., 2013 Jul;45:825-30). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation.

CDKL5 disorder Pathogenic:1

Sep 20, 2024

Centre for Population Genomics, CPG

Significance: Pathogenic

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 pathogenic. At least the following criteria are met: Predicted to result in loss of function, and LOF is a known mechanism of disease (PVS1). This variant is absent from gnomAD v4 (PM2_Supporting). Has been observed in at least 2 individuals with phenotypes consistent with CDKL5 disorder (PS4_Supporting). PubMed: 16015284‚ 23708187, Variation ID: 156090.

not provided Other:1

RettBASE

Significance: not provided

Review Status: flagged submission

Collection Method: literature only

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.060
CADD	Pathogenic	34
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0	.;.;.;.;.;.
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.0	.;.;.;.;.;.
MetaRNN	Benign	0.0	.;.;.;.;.;.
MutationAssessor	Benign	0.0	.;.;.;.;.;.
PhyloP100		9.3
PROVEAN	Benign	0.0	.;.;.;.;.;.
REVEL	Benign	0.0
Sift	Pathogenic	0.0	.;.;.;.;.;.
Sift4G	Pathogenic	0.0	.;.;.;.;.;.
Vest4		0.0
GERP RS		5.7
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.76		Position offset: -27
DS_AL_spliceai		0.99		Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs267608480; hg19: chrX-18602381; COSMIC: COSV66113787; COSMIC: COSV66113787;