rs587783072

chrX-18575419-A-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Moderate

The NM_001323289.2(CDKL5):c.211A>G(p.Asn71Asp) variant causes a missense change involving the alteration of a 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N71K) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 23)
• Consequence: CDKL5 NM_001323289.2 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 9.32

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 Pathogenic. Variant got 12 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 4 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-18575421-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 803715.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.985
• PP5: Variant X-18575419-A-G is Pathogenic according to our data. Variant chrX-18575419-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 156591.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDKL5	NM_001323289.2	c.211A>G	p.Asn71Asp	missense_variant	5/18	ENST00000623535.2
CDKL5	NM_001037343.2	c.211A>G	p.Asn71Asp	missense_variant	6/22
CDKL5	NM_003159.3	c.211A>G	p.Asn71Asp	missense_variant	5/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDKL5	ENST00000623535.2	c.211A>G	p.Asn71Asp	missense_variant	5/18	1	NM_001323289.2	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Sep 19, 2013

The Asn71Asp missense mutation in the CDKL5 gene has been reported previously as a de novo mutation in a female with the early-onset seizure variant of Rett syndrome (Artuso et al., 2010). It is a non-conservative amino acid substitution of an uncharged Asparagine residue with a negatively charged Aspartic acid residue at a position that is conserved across species. The variant is found in EPILEPSY panel(s). -

Atypical Rett syndrome Pathogenic:1

Likely pathogenic, no assertion criteria provided

curation

RettBASE

Mar 13, 2014

Highly conserved amino acid in catalytic domain; 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	0.97
BayesDel_addAF	Uncertain	0.043	T
BayesDel_noAF	Benign	-0.18
Cadd	Pathogenic	27
Dann	Uncertain	1.0
DEOGEN2	Benign	0.26	T;T;.;T;.;.
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.89	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D
MetaSVM	Uncertain	0.14	D
MutationAssessor	Pathogenic	3.1	M;.;.;M;.;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-4.9	D;.;.;D;.;.
REVEL	Uncertain	0.58
Sift	Uncertain	0.0020	D;.;.;D;.;.
Sift4G	Uncertain	0.0060	D;.;.;D;D;D
Polyphen		1.0	D;.;.;D;.;.
Vest4		0.95
MutPred		0.96		Loss of MoRF binding (P = 0.0367);Loss of MoRF binding (P = 0.0367);Loss of MoRF binding (P = 0.0367);Loss of MoRF binding (P = 0.0367);Loss of MoRF binding (P = 0.0367);Loss of MoRF binding (P = 0.0367);
MVP		0.86
MPC		2.6
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.98
gMVP		0.99

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: rs587783072; hg19: chrX-18593539;