NM_001323289.2:c.872G>A

Variant names:

• chrX-18598508-G-A
• rs267606714
• NM_001323289.2:c.872G>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM6 PS4_Supporting PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The p.Cys291Tyr variant in CDKL5 has been reported as a de novo occurrence (biological parentage unconfirmed) in an individual with severe early-onset encephalopathy (PMID 18809835) (PM6). The p.Cys291Tyr variant in CDKL5 is absent from gnomAD (PM2_Supporting). The p.Cys291Tyr variant has been observed in at least 1 other individual with CDKL5-related disorder (PMID 18809835, PMID 25657822) (PS4_Supporting). In summary, the p.Cys291Tyr variant in CDKL5 is classified as a variant of unknown significance based on the ACMG/AMP criteria (PM6, PM2_Supporting, PS4_Supporting). LINK:https://erepo.genome.network/evrepo/ui/classification/CA121527/MONDO:0100039/016

• Frequency: Genomes: not found (cov: 23)
• Consequence: CDKL5 NM_001323289.2 missense
• Clinical Significance: Uncertain significance reviewed by expert panel P:1 U:4
• Conservation: PhyloP100: 9.36
• Publications: 8 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 4 ACMG points.

• 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDKL5	NM_001323289.2	MANE Select	c.872G>A	p.Cys291Tyr	missense	Exon 11 of 18	NP_001310218.1
	CDKL5	NM_001037343.2		c.872G>A	p.Cys291Tyr	missense	Exon 12 of 22	NP_001032420.1
	CDKL5	NM_003159.3		c.872G>A	p.Cys291Tyr	missense	Exon 11 of 21	NP_003150.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDKL5	ENST00000623535.2	TSL:1 MANE Select	c.872G>A	p.Cys291Tyr	missense	Exon 11 of 18	ENSP00000485244.1
	CDKL5	ENST00000379989.6	TSL:1	c.872G>A	p.Cys291Tyr	missense	Exon 12 of 22	ENSP00000369325.3
	CDKL5	ENST00000379996.7	TSL:1	c.872G>A	p.Cys291Tyr	missense	Exon 11 of 21	ENSP00000369332.3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	2	-	CDKL5 disorder (2)
1	1	-	Developmental and epileptic encephalopathy, 2 (2)
-	1	-	Developmental and epileptic encephalopathy, 2;CN128785:Angelman syndrome-like (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.21	T
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.90	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Benign	-0.44	T
MutationAssessor	Benign	1.6	L
PhyloP100		9.4
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-6.1	D
REVEL	Pathogenic	0.71
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.030	D
Polyphen		1.0	D
Vest4		0.86
MutPred		0.87		Gain of phosphorylation at C291 (P = 0.0469)
MVP		0.93
MPC		1.2
ClinPred		0.99	D
GERP RS		5.5
Varity_R		0.99
gMVP		0.93
Mutation Taster		=3/97	disease causing

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: rs267606714; hg19: chrX-18616628;