chrX-18625241-G-T

Position:

• chrX-18625241-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000623535.2(CDKL5):​c.2490G>T​(p.Gln830His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar.

• Frequency: Genomes: not found (cov: 21)
• Consequence: CDKL5 ENST00000623535.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.29

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12942249).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDKL5	NM_001323289.2	c.2490G>T	p.Gln830His	missense_variant	17/18	ENST00000623535.2	NP_001310218.1
CDKL5	NM_001037343.2	c.2490G>T	p.Gln830His	missense_variant	18/22		NP_001032420.1
CDKL5	NM_003159.3	c.2490G>T	p.Gln830His	missense_variant	17/21		NP_003150.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDKL5	ENST00000623535.2	c.2490G>T	p.Gln830His	missense_variant	17/18	1	NM_001323289.2	ENSP00000485244	P1

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 21

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.070	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	13
DANN	Benign	0.95
DEOGEN2	Benign	0.022	T;T;T;.
FATHMM_MKL	Benign	0.56	D
LIST_S2	Benign	0.16	.;T;T;T
M_CAP	Pathogenic	0.40	D
MetaRNN	Benign	0.13	T;T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.1	L;.;L;L
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.17	N;.;N;.
REVEL	Benign	0.27
Sift	Benign	0.069	T;.;T;.
Sift4G	Benign	0.45	T;.;T;T
Polyphen		0.016	B;.;B;.
Vest4		0.32
MutPred		0.046		Loss of MoRF binding (P = 0.1185);Loss of MoRF binding (P = 0.1185);Loss of MoRF binding (P = 0.1185);Loss of MoRF binding (P = 0.1185);
MVP		0.91
MPC		0.45
ClinPred		0.13	T
GERP RS		1.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.15
gMVP		0.31

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: rs1485485459; hg19: chrX-18643361;