rs1279388510

Positions:

• chrX-18604018-G-A
• chrX-18604018-G-C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001323289.2(CDKL5):​c.1094G>A​(p.Ser365Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00000331 in 1,209,363 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a benign 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. S365T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000018 (0 hom., 2 hem., cov: 23)
  • Exomes 𝑓: 0.0000018 (0 hom. 0 hem.)
• Consequence: CDKL5 NM_001323289.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 3.77

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 -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.19826627).
• BS2: High Hemizygotes in GnomAd4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDKL5	NM_001323289.2	c.1094G>A	p.Ser365Asn	missense_variant	12/18	ENST00000623535.2
CDKL5	NM_001037343.2	c.1094G>A	p.Ser365Asn	missense_variant	13/22
CDKL5	NM_003159.3	c.1094G>A	p.Ser365Asn	missense_variant	12/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDKL5	ENST00000623535.2	c.1094G>A	p.Ser365Asn	missense_variant	12/18	1	NM_001323289.2	P1

Frequencies

GnomAD3 genomes AF: 0.0000180 AC: 2 AN: 111109 Hom.: 0 Cov.: 23 AF XY: 0.0000600 AC XY: 2 AN XY: 33339

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000767

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000109 AC: 2 AN: 183462 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 67892

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000244

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000182 AC: 2 AN: 1098202 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 363556

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000238

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000180 AC: 2 AN: 111161 Hom.: 0 Cov.: 23 AF XY: 0.0000599 AC XY: 2 AN XY: 33401

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000769

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Nov 01, 2023

CDKL5: PM2 -

Developmental and epileptic encephalopathy, 2;CN128785:Angelman syndrome-like Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 11, 2023

This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 365 of the CDKL5 protein (p.Ser365Asn). This variant is present in population databases (no rsID available, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with CDKL5-related conditions. ClinVar contains an entry for this variant (Variation ID: 1503908). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CDKL5 protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.041	T;T;.;T;.;.
FATHMM_MKL	Uncertain	0.95	D
M_CAP	Pathogenic	0.59	D
MetaRNN	Benign	0.20	T;T;T;T;T;T
MetaSVM	Benign	-0.45	T
MutationAssessor	Benign	1.2	L;.;.;L;.;L
MutationTaster	Benign	0.85	D;D
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.85	N;.;.;N;.;.
REVEL	Benign	0.085
Sift	Uncertain	0.0010	D;.;.;D;.;.
Sift4G	Benign	0.073	T;.;.;T;T;T
Polyphen		0.88	P;.;.;P;.;.
Vest4		0.19
MutPred		0.21		Loss of glycosylation at S365 (P = 0.2269);Loss of glycosylation at S365 (P = 0.2269);Loss of glycosylation at S365 (P = 0.2269);Loss of glycosylation at S365 (P = 0.2269);Loss of glycosylation at S365 (P = 0.2269);Loss of glycosylation at S365 (P = 0.2269);
MVP		0.77
MPC		0.44
ClinPred		0.34	T
GERP RS		5.2
Varity_R		0.62
gMVP		0.53

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: rs1279388510; hg19: chrX-18622138;