rs587783405

Variant names:

• chrX-18588021-C-T
• rs587783405
• NM_001323289.2:c.622C>T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001323289.2(CDKL5):​c.622C>T​(p.Gln208*) variant causes a stop gained 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. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 23)
• Consequence: CDKL5 NM_001323289.2 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 7.57
• Publications: 1 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 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-18588021-C-T is Pathogenic according to our data. Variant chrX-18588021-C-T is described in CliVar as Pathogenic. Clinvar id is 158186.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-18588021-C-T is described in CliVar as Pathogenic. Clinvar id is 158186.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-18588021-C-T is described in CliVar as Pathogenic. Clinvar id is 158186.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-18588021-C-T is described in CliVar as Pathogenic. Clinvar id is 158186.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-18588021-C-T is described in CliVar as Pathogenic. Clinvar id is 158186.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-18588021-C-T is described in CliVar as Pathogenic. Clinvar id is 158186.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-18588021-C-T is described in CliVar as Pathogenic. Clinvar id is 158186.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-18588021-C-T is described in CliVar as Pathogenic. Clinvar id is 158186.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-18588021-C-T is described in CliVar as Pathogenic. Clinvar id is 158186.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-18588021-C-T is described in CliVar as Pathogenic. Clinvar id is 158186.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.622C>T	p.Gln208*	stop_gained	Exon 9 of 18	ENST00000623535.2	NP_001310218.1
CDKL5	NM_001037343.2	c.622C>T	p.Gln208*	stop_gained	Exon 10 of 22		NP_001032420.1
CDKL5	NM_003159.3	c.622C>T	p.Gln208*	stop_gained	Exon 9 of 21		NP_003150.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDKL5	ENST00000623535.2	c.622C>T	p.Gln208*	stop_gained	Exon 9 of 18	1	NM_001323289.2	ENSP00000485244.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Developmental and epileptic encephalopathy, 2 Pathogenic:1

May 06, 2014

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Bruxism;C0036572:Seizure;C0038273:Stereotypic movement disorder;C0454644:Delayed speech and language development;C0557874:Global developmental delay;C0562479:Stereotypical hand wringing;C1858120:Generalized hypotonia;C4023013:Stereotypical body rocking Pathogenic:1

Jan 01, 2017

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.66
CADD	Pathogenic	37
DANN	Uncertain	1.0
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		7.6
Vest4		0.90
GERP RS		6.1
Mutation Taster		=0/200	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs587783405; hg19: chrX-18606141;