rs786204961

Variant names:

• chrX-18584272-G-A
• rs757402424
• NM_001323289.2:c.473G>A

Your query was ambiguous. Multiple possible variants found:

• chrX-18584272-G-A
• chrX-18584272-G-C

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1 PM2 PM5 PP3_Moderate

The NM_001323289.2(CDKL5):​c.473G>A​(p.Arg158His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000185 in 1,083,879 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R158P) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000018 (0 hom. 0 hem.)
• Consequence: CDKL5 NM_001323289.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 10.0
• Publications: 4 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: Likely_pathogenic. The variant received 8 ACMG points.

• PM1: In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_001323289.2
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-18584272-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 189547.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.9

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.473G>A	p.Arg158His	missense	Exon 8 of 18	NP_001310218.1	O76039-2
	CDKL5	NM_001037343.2		c.473G>A	p.Arg158His	missense	Exon 9 of 22	NP_001032420.1	O76039-1
	CDKL5	NM_003159.3		c.473G>A	p.Arg158His	missense	Exon 8 of 21	NP_003150.1	O76039-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDKL5	ENST00000623535.2	TSL:1 MANE Select	c.473G>A	p.Arg158His	missense	Exon 8 of 18	ENSP00000485244.1	O76039-2
	CDKL5	ENST00000379989.6	TSL:1	c.473G>A	p.Arg158His	missense	Exon 9 of 22	ENSP00000369325.3	O76039-1
	CDKL5	ENST00000379996.7	TSL:1	c.473G>A	p.Arg158His	missense	Exon 8 of 21	ENSP00000369332.3	O76039-1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD2 exomes AF: 0.0000109 AC: 2 AN: 183121 AF XY: 0.00

Gnomad AFR exome AF: 0.000152

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: 0.00000185 AC: 2 AN: 1083879 Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0 AN XY: 350569

African (AFR) AF: 0.0000766 AC: 2 AN: 26104

American (AMR) AF: 0.00 AC: 0 AN: 35175

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19308

East Asian (EAS) AF: 0.00 AC: 0 AN: 30155

South Asian (SAS) AF: 0.00 AC: 0 AN: 53817

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40515

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4094

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 829103

Other (OTH) AF: 0.00 AC: 0 AN: 45608

GnomAD4 genome Cov.: 23

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000227

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.20	T
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.81	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Uncertain	0.35	D
MutationAssessor	Uncertain	2.9	M
PhyloP100		10
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-5.0	D
REVEL	Pathogenic	0.75
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.98
MVP		0.93
MPC		2.8
ClinPred		0.98	D
GERP RS		5.7
Varity_R		0.99
gMVP		0.89
Mutation Taster		=59/41	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs757402424; hg19: chrX-18602392;