chrX-18604324-A-C

Variant names:

• chrX-18604324-A-C
• rs267608631
• NM_001323289.2:c.1400A>C

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 (★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: CDKL5 NM_001323289.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• 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 rank	MANE	Protein	UniProt
CDKL5	NM_001323289.2	c.1400A>C	p.His467Pro	missense_variant	Exon 12 of 18	ENST00000623535.2	NP_001310218.1
CDKL5	NM_001037343.2	c.1400A>C	p.His467Pro	missense_variant	Exon 13 of 22		NP_001032420.1
CDKL5	NM_003159.3	c.1400A>C	p.His467Pro	missense_variant	Exon 12 of 21		NP_003150.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDKL5	ENST00000623535.2	c.1400A>C	p.His467Pro	missense_variant	Exon 12 of 18	1	NM_001323289.2	ENSP00000485244.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 22

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

Developmental and epileptic encephalopathy, 2 Uncertain:1

Mar 13, 2014

RettBASE

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: curation

- -

CDKL5 disorder Uncertain:1

Sep 13, 2024

Centre for Population Genomics, CPG

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

This variant has been collected from RettBASE and curated to current modified ACMG/AMP criteria. Based on the classification scheme defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like Disorders Specifications to the ACMG/AMP Variant Interpretation Guidelines VCEP 3.0, this variant is classified as a variant of uncertain significance. At least the following criteria are met: This variant is absent from gnomAD (PM2_Supporting). The variant has been observed in cis with a CDKL5 pathogenic variant (BP2, PMID: 21770923) -

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
LIST_S2	Uncertain	0.90	.;D;D;D;D;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
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;