rs786204991

chrX-18510846-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP3_Moderate PP5

The NM_001323289.2(CDKL5):c.91A>G(p.Arg31Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. R31R) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: CDKL5 NM_001323289.2 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 4.27

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_pathogenic. Variant got 7 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_001323289.2
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.858
• PP5: Variant X-18510846-A-G is Pathogenic according to our data. Variant chrX-18510846-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 189599.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDKL5	NM_001323289.2	c.91A>G	p.Arg31Gly	missense_variant	3/18	ENST00000623535.2
CDKL5	NM_001037343.2	c.91A>G	p.Arg31Gly	missense_variant	4/22
CDKL5	NM_003159.3	c.91A>G	p.Arg31Gly	missense_variant	3/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDKL5	ENST00000623535.2	c.91A>G	p.Arg31Gly	missense_variant	3/18	1	NM_001323289.2	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1061552 Hom.: 0 Cov.: 24 AF XY: 0.00 AC XY: 0 AN XY: 332160

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Developmental and epileptic encephalopathy, 2 Pathogenic:1

Pathogenic, no assertion criteria provided

curation

RettBASE

Mar 13, 2014

De novo mutation; In silico prediction: SIFT = deleterious, MutationTaster = disease-causing, PolyPhen2 = probably damaging, AlignGVGD = benign (C0) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.17
Cadd	Pathogenic	27
Dann	Uncertain	1.0
DEOGEN2	Benign	0.20	T;T;.;T;.;.;.;.
FATHMM_MKL	Uncertain	0.93	D
M_CAP	Pathogenic	0.70	D
MetaRNN	Pathogenic	0.86	D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.44	T
MutationAssessor	Pathogenic	3.0	M;.;.;M;.;.;.;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-4.7	D;.;.;D;.;.;.;.
REVEL	Uncertain	0.45
Sift	Pathogenic	0.0	D;.;.;D;.;.;.;.
Sift4G	Uncertain	0.0020	D;.;.;D;D;D;D;D
Polyphen		0.99	D;.;.;D;.;.;.;.
Vest4		0.89
MutPred		0.72		Loss of stability (P = 0.0159);Loss of stability (P = 0.0159);Loss of stability (P = 0.0159);Loss of stability (P = 0.0159);Loss of stability (P = 0.0159);Loss of stability (P = 0.0159);Loss of stability (P = 0.0159);Loss of stability (P = 0.0159);
MVP		0.97
MPC		2.4
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.98
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs786204991; hg19: chrX-18528966;