rs267608490

Variant names:

• chrX-18584312-C-A
• rs267608490
• NM_001323289.2:c.513C>A

Your query was ambiguous. Multiple possible variants found:

• chrX-18584312-C-A
• chrX-18584312-C-G
• chrX-18584312-C-T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM6 PVS1 PS4_Supporting PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The p.Tyr171* variant in CDKL5 is predicted to cause a premature stop codon that leads to a truncated or absent protein in a gene where loss-of-function is an established mechanism. There is significant evidence that loss of this region of the gene is pathogenic (PVS1). The p.Tyr171* variant in CDKL5 has been reported as a de novo occurrence (biological parentage unconfirmed) in an individual with CDKL5 disorder (PMID 23583054) (PM6. This variant has been observed in at least 1 other individual with CDKL5 disorder (ClinVar) (PS4_Supporting). This variant was absent from gnomAD (PM2_ Supporting). In summary, p.Tyr171* variant in CDKL5 is classified as Pathogenic for CDKL5 disorder based on the ACMG/AMP criteria (PVS1, PM6, PM2_Supporting, PS4_Supporting). LINK:https://erepo.genome.network/evrepo/ui/classification/CA171644/MONDO:0100039/016

• Frequency: Genomes: not found (cov: 23)
• Consequence: CDKL5 NM_001323289.2 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:6
• Conservation: PhyloP100: 0.868
• Publications: 6 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: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM6: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001323289.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDKL5	NM_001323289.2	MANE Select	c.513C>A	p.Tyr171*	stop_gained	Exon 8 of 18	NP_001310218.1
	CDKL5	NM_001037343.2		c.513C>A	p.Tyr171*	stop_gained	Exon 9 of 22	NP_001032420.1
	CDKL5	NM_003159.3		c.513C>A	p.Tyr171*	stop_gained	Exon 8 of 21	NP_003150.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDKL5	ENST00000623535.2	TSL:1 MANE Select	c.513C>A	p.Tyr171*	stop_gained	Exon 8 of 18	ENSP00000485244.1
	CDKL5	ENST00000379989.6	TSL:1	c.513C>A	p.Tyr171*	stop_gained	Exon 9 of 22	ENSP00000369325.3
	CDKL5	ENST00000379996.7	TSL:1	c.513C>A	p.Tyr171*	stop_gained	Exon 8 of 21	ENSP00000369332.3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
2	-	-	CDKL5 disorder (2)
2	-	-	Developmental and epileptic encephalopathy, 2 (2)
1	-	-	Developmental and epileptic encephalopathy, 2;CN128785:Angelman syndrome-like (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	34
DANN	Uncertain	1.0
FATHMM_MKL	Uncertain	0.85	D
PhyloP100		0.87
Vest4		0.83
GERP RS		0.48
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.39		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.39		Position offset: -4

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

Other links and lift over

dbSNP: rs267608490; hg19: chrX-18602432;