rs267608631

chrX-18604324-A-CchrX-18604324-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001323289.2(CDKL5):c.1400A>C(p.His467Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H467R) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 22)
• Consequence: CDKL5 NM_001323289.2 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 7.01

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDKL5	NM_001323289.2	c.1400A>C	p.His467Pro	missense_variant	12/18	ENST00000623535.2
CDKL5	NM_001037343.2	c.1400A>C	p.His467Pro	missense_variant	13/22
CDKL5	NM_003159.3	c.1400A>C	p.His467Pro	missense_variant	12/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDKL5	ENST00000623535.2	c.1400A>C	p.His467Pro	missense_variant	12/18	1	NM_001323289.2	P1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 22

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

Developmental and epileptic encephalopathy, 2 Uncertain:1

Uncertain significance, no assertion criteria provided

curation

RettBASE

Mar 13, 2014

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.30
Cadd	Uncertain	24
Dann	Uncertain	0.99
DEOGEN2	Benign	0.19	T;T;.;T;.;.
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.74	D
MetaRNN	Uncertain	0.68	D;D;D;D;D;D
MetaSVM	Uncertain	-0.013	T
MutationAssessor	Uncertain	2.3	M;.;.;M;.;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-3.6	D;.;.;D;.;.
REVEL	Uncertain	0.47
Sift	Uncertain	0.0010	D;.;.;D;.;.
Sift4G	Uncertain	0.027	D;.;.;D;T;T
Polyphen		1.0	D;.;.;D;.;.
Vest4		0.81
MutPred		0.19		Gain of glycosylation at H467 (P = 0.047);Gain of glycosylation at H467 (P = 0.047);Gain of glycosylation at H467 (P = 0.047);Gain of glycosylation at H467 (P = 0.047);Gain of glycosylation at H467 (P = 0.047);Gain of glycosylation at H467 (P = 0.047);
MVP		0.90
MPC		0.71
ClinPred		0.93	D
GERP RS		6.1
Varity_R		0.84
gMVP		0.39

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

Publications

LitVar

Other links and lift over

dbSNP: rs267608631; hg19: chrX-18622444;