rs144204039

Positions:

• chrX-18603995-C-G
• chrX-18603995-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001323289.2(CDKL5):​c.1071C>G​(p.Asp357Glu) 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. 15/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 22)
• Consequence: CDKL5 NM_001323289.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.69

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.009116203).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDKL5	NM_001323289.2	c.1071C>G	p.Asp357Glu	missense_variant	12/18	ENST00000623535.2	NP_001310218.1
CDKL5	NM_001037343.2	c.1071C>G	p.Asp357Glu	missense_variant	13/22		NP_001032420.1
CDKL5	NM_003159.3	c.1071C>G	p.Asp357Glu	missense_variant	12/21		NP_003150.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDKL5	ENST00000623535.2	c.1071C>G	p.Asp357Glu	missense_variant	12/18	1	NM_001323289.2	ENSP00000485244	P1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 22

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.0010
DANN	Benign	0.70
DEOGEN2	Benign	0.017	T;T;.;T;.;.
FATHMM_MKL	Benign	0.047	N
LIST_S2	Benign	0.65	.;T;T;T;T;T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.0091	T;T;T;T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-2.2	N;.;.;N;.;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.020	N;.;.;N;.;.
REVEL	Benign	0.14
Sift	Benign	0.70	T;.;.;T;.;.
Sift4G	Benign	0.74	T;.;.;T;T;T
Polyphen		0.0020	B;.;.;B;.;.
Vest4		0.073
MutPred		0.18		Gain of disorder (P = 0.3363);Gain of disorder (P = 0.3363);Gain of disorder (P = 0.3363);Gain of disorder (P = 0.3363);Gain of disorder (P = 0.3363);Gain of disorder (P = 0.3363);
MVP		0.29
MPC		0.32
ClinPred		0.061	T
GERP RS		-12
Varity_R		0.072
gMVP		0.062

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: rs144204039; hg19: chrX-18622115;