X-18628470-C-T

Variant names:

• chrX-18628470-C-T
• rs587783158
• NM_001323289.2:c.2596C>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.2596C>T​(p.Gln866*) variant causes a stop gained change. 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 (★★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: CDKL5 NM_001323289.2 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 4.19
• Publications: 2 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 does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 24 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-18628470-C-T is Pathogenic according to our data. Variant chrX-18628470-C-T is described in CliVar as Pathogenic. Clinvar id is 156691.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-18628470-C-T is described in CliVar as Pathogenic. Clinvar id is 156691.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-18628470-C-T is described in CliVar as Pathogenic. Clinvar id is 156691.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-18628470-C-T is described in CliVar as Pathogenic. Clinvar id is 156691.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-18628470-C-T is described in CliVar as Pathogenic. Clinvar id is 156691.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-18628470-C-T is described in CliVar as Pathogenic. Clinvar id is 156691.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-18628470-C-T is described in CliVar as Pathogenic. Clinvar id is 156691.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.2596C>T	p.Gln866*	stop_gained	Exon 18 of 18	ENST00000623535.2	NP_001310218.1
CDKL5	NM_001037343.2	c.2596C>T	p.Gln866*	stop_gained	Exon 19 of 22		NP_001032420.1
CDKL5	NM_003159.3	c.2596C>T	p.Gln866*	stop_gained	Exon 18 of 21		NP_003150.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDKL5	ENST00000623535.2	c.2596C>T	p.Gln866*	stop_gained	Exon 18 of 18	1	NM_001323289.2	ENSP00000485244.1
CDKL5	ENST00000379989.6	c.2596C>T	p.Gln866*	stop_gained	Exon 19 of 22	1		ENSP00000369325.3
CDKL5	ENST00000379996.7	c.2596C>T	p.Gln866*	stop_gained	Exon 18 of 21	1		ENSP00000369332.3
CDKL5	ENST00000674046.1	c.2719C>T	p.Gln907*	stop_gained	Exon 19 of 19			ENSP00000501174.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 22

Alfa AF: 0.0000427 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Developmental and epileptic encephalopathy, 2 Pathogenic:1

Nov 16, 2012

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:1

Apr 12, 2012

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Gln866Stop nonsense mutation in the CDKL5 gene is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The variant is found in EPILEPSY panel(s). -

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

Oct 21, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Gln866*) in the CDKL5 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CDKL5 are known to be pathogenic (PMID: 22872100). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with CDKL5-related conditions (PMID: 29655203). ClinVar contains an entry for this variant (Variation ID: 156691). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.66
CADD	Pathogenic	36
DANN	Uncertain	1.0
FATHMM_MKL	Pathogenic	0.97	D
PhyloP100		4.2
Vest4		0.84
GERP RS		5.7
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs587783158; hg19: chrX-18646590;