rs770340766

chrX-18604158-A-G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PM2 BP6_Very_Strong

The NM_001323289.2(CDKL5):c.1234A>G(p.Lys412Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000911 in 1,098,157 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. Variant has been reported in ClinVar as Likely benign (★★★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.1e-7 (0 hom. 1 hem.)
• Consequence: CDKL5 NM_001323289.2 missense
• Clinical Significance: Likely benign reviewed by expert panel U:1 B:2
• Conservation: PhyloP100: 8.94

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.

• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant X-18604158-A-G is Benign according to our data. Variant chrX-18604158-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 423898.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDKL5	NM_001323289.2	c.1234A>G	p.Lys412Glu	missense_variant	12/18	ENST00000623535.2
CDKL5	NM_001037343.2	c.1234A>G	p.Lys412Glu	missense_variant	13/22
CDKL5	NM_003159.3	c.1234A>G	p.Lys412Glu	missense_variant	12/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDKL5	ENST00000623535.2	c.1234A>G	p.Lys412Glu	missense_variant	12/18	1	NM_001323289.2	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD3 exomes AF: 0.00000546 AC: 1 AN: 183091 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 67661

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: 0.0000123

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 9.11e-7 AC: 1 AN: 1098157 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 1 AN XY: 363513

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: 0.00000119

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

Bravo AF: 0.00000756

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:1 Benign:2

Revision: reviewed by expert panel

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 07, 2023

ClinVar contains an entry for this variant (Variation ID: 423898). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on CDKL5 protein function. This variant has not been reported in the literature in individuals affected with CDKL5-related conditions. This variant is present in population databases (rs770340766, gnomAD 0.001%). This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 412 of the CDKL5 protein (p.Lys412Glu). 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. -

CDKL5 disorder Benign:1

Likely benign, reviewed by expert panel

curation

ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel

Aug 28, 2023

The p.Lys412Glu variant in CDKL5 is present in 1 XY individual in gnomAD (0.0001707%) (not sufficient to meet BS1 criteria). The p.Lys412Glu variant is observed in at least 2 unaffected individuals (internal database - GeneDx) (BS2). Computational analysis prediction tools suggests that the p.Lys412Glu variant does not have a deleterious impact (BP4); however this information does not predict clinical significance on its own. In summary, the p.Lys412Glu variant in CDKL5 is classified as likely benign based on the ACMG/AMP criteria (BS2, BP4). -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Apr 11, 2022

See Variant Classification Assertion Criteria. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Benign	0.053	T;T;.;T;.;.
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.59	D
MetaRNN	Uncertain	0.50	D;D;D;D;D;D
MetaSVM	Uncertain	-0.18	T
MutationAssessor	Uncertain	2.3	M;.;.;M;.;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-1.9	N;.;.;N;.;.
REVEL	Uncertain	0.41
Sift	Uncertain	0.0010	D;.;.;D;.;.
Sift4G	Uncertain	0.032	D;.;.;D;T;T
Polyphen		1.0	D;.;.;D;.;.
Vest4		0.76
MutPred		0.16		Loss of ubiquitination at K412 (P = 0.0077);Loss of ubiquitination at K412 (P = 0.0077);Loss of ubiquitination at K412 (P = 0.0077);Loss of ubiquitination at K412 (P = 0.0077);Loss of ubiquitination at K412 (P = 0.0077);Loss of ubiquitination at K412 (P = 0.0077);
MVP		0.94
MPC		0.70
ClinPred		0.70	D
GERP RS		6.1
Varity_R		0.75
gMVP		0.52

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: rs770340766; hg19: chrX-18622278;