rs61749700

chrX-18584324-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PM5 PP3_Moderate PP5

The NM_001323289.2(CDKL5):c.525A>T(p.Arg175Ser) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R175G) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 23)
• Consequence: CDKL5 NM_001323289.2 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 0.804

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 9 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_001323289.2
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-18584322-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 983042.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.938
• PP5: Variant X-18584324-A-T is Pathogenic according to our data. Variant chrX-18584324-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 11497.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chrX-18584324-A-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDKL5	NM_001323289.2	c.525A>T	p.Arg175Ser	missense_variant	8/18	ENST00000623535.2
CDKL5	NM_001037343.2	c.525A>T	p.Arg175Ser	missense_variant	9/22
CDKL5	NM_003159.3	c.525A>T	p.Arg175Ser	missense_variant	8/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDKL5	ENST00000623535.2	c.525A>T	p.Arg175Ser	missense_variant	8/18	1	NM_001323289.2	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

Submissions by phenotype

Developmental and epileptic encephalopathy, 2 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 01, 2004

- -

Atypical Rett syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

curation

RettBASE

Mar 13, 2014

In vitro study (Ricciardi et al 2009) shows abnormal nuclear speckles; 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	0.25	D
BayesDel_noAF	Uncertain	0.12
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.22	T;T;.;T;.;.
FATHMM_MKL	Uncertain	0.83	D
M_CAP	Pathogenic	0.29	D
MetaRNN	Pathogenic	0.94	D;D;D;D;D;D
MetaSVM	Benign	-0.55	T
MutationAssessor	Uncertain	2.1	M;.;.;M;.;M
MutationTaster	Benign	1.0	A;A
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-6.0	D;.;.;D;.;.
REVEL	Uncertain	0.61
Sift	Pathogenic	0.0	D;.;.;D;.;.
Sift4G	Pathogenic	0.0010	D;.;.;D;D;D
Polyphen		1.0	D;.;.;D;.;.
Vest4		0.98
MutPred		0.84		Gain of sheet (P = 0.1945);Gain of sheet (P = 0.1945);Gain of sheet (P = 0.1945);Gain of sheet (P = 0.1945);Gain of sheet (P = 0.1945);Gain of sheet (P = 0.1945);
MVP		0.98
MPC		2.6
ClinPred		1.0	D
GERP RS		1.3
Varity_R		0.99
gMVP		0.96

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: rs61749700; hg19: chrX-18602444;