rs267608473

Variant names:

• chrX-18580013-AAAGTT-A
• rs267608473
• NM_001323289.2:c.403+49_403+53delTTAAG

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP6_Moderate

The NM_001323289.2(CDKL5):​c.403+49_403+53delTTAAG variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000213 in 939,021 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000021 (0 hom. 0 hem.)
• Consequence: CDKL5 NM_001323289.2 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:2 O:1
• Conservation: PhyloP100: 1.69
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant X-18580013-AAAGTT-A is Benign according to our data. Variant chrX-18580013-AAAGTT-A is described in ClinVar as Likely_benign. ClinVar VariationId is 156086.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDKL5	NM_001323289.2	c.403+49_403+53delTTAAG		intron_variant	Intron 6 of 17	ENST00000623535.2	NP_001310218.1
CDKL5	NM_001037343.2	c.403+49_403+53delTTAAG		intron_variant	Intron 7 of 21		NP_001032420.1
CDKL5	NM_003159.3	c.403+49_403+53delTTAAG		intron_variant	Intron 6 of 20		NP_003150.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDKL5	ENST00000623535.2	c.403+46_403+50delAAGTT		intron_variant	Intron 6 of 17	1	NM_001323289.2	ENSP00000485244.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD2 exomes AF: 0.00000557 AC: 1 AN: 179530 AF XY: 0.00

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000213 AC: 2 AN: 939021 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 258455

African (AFR) AF: 0.00 AC: 0 AN: 23368

American (AMR) AF: 0.00 AC: 0 AN: 34771

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18222

East Asian (EAS) AF: 0.00 AC: 0 AN: 29305

South Asian (SAS) AF: 0.0000200 AC: 1 AN: 49970

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40176

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3753

European-Non Finnish (NFE) AF: 0.00000143 AC: 1 AN: 698705

Other (OTH) AF: 0.00 AC: 0 AN: 40751

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Likely benign

Submissions summary: Benign:2 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Mar 13, 2014

RettBASE

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: curation

No splicing effect predicted, but not empirically tested -

CDKL5 disorder Benign:1

Jul 16, 2024

Centre for Population Genomics, CPG

Significance: Likely 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 likely benign. At least the following criteria are met: Synonymous or intronic variant outside donor and acceptor splice regions where splicing prediction algorithms do not support significant splicing alteration (spliceAI score <=0.1) (BP4, BP7). -

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
PhyloP100		1.7

Splicing

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

Other links and lift over

dbSNP: rs267608473; hg19: chrX-18598133;