rs267608653

Positions:

• chrX-18609570-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_001323289.2(CDKL5):​c.2152G>A​(p.Val718Met) variant causes a missense, splice region 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. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 23)
• Consequence: CDKL5 NM_001323289.2 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 9.33

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.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.
• PP5: Variant X-18609570-G-A is Pathogenic according to our data. Variant chrX-18609570-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 143796.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1}. Variant chrX-18609570-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDKL5	NM_001323289.2	c.2152G>A	p.Val718Met	missense_variant, splice_region_variant	14/18	ENST00000623535.2	NP_001310218.1
CDKL5	NM_001037343.2	c.2152G>A	p.Val718Met	missense_variant, splice_region_variant	15/22		NP_001032420.1
CDKL5	NM_003159.3	c.2152G>A	p.Val718Met	missense_variant, splice_region_variant	14/21		NP_003150.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDKL5	ENST00000623535.2	c.2152G>A	p.Val718Met	missense_variant, splice_region_variant	14/18	1	NM_001323289.2	ENSP00000485244	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 23

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Developmental and epileptic encephalopathy, 2 Pathogenic:1

Likely pathogenic, no assertion criteria provided

curation

RettBASE

Mar 13, 2014

No parental studies; highly conserved residue; In silico prediction: SIFT = deleterious, MutationTaster = disease-causing, PolyPhen2 = probably damaging, AlignGVGD = benign (C0) -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 19, 2014

The V718M missense mutation in the CDKL5 gene has been reported previously as a de novo mutation in a patient with infantile spasms, microcephaly with deceleration of head growth, severe intellectual disability, and limited hand skills (Bahi-Buisson et al., 2008). This mutation alters a highly conserved position in the C-terminal region of the protein. The variant is found in INFANT-EPI panel(s). -

CDKL5 disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

curation

Centre for Population Genomics, CPG

Sep 16, 2024

This variant has been collected from RettBASE and curated to current modified ACMG/AMP criteria. Based on the classification scheme defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like Disorders Specifications to the ACMG/AMP Variant Interpretation Guidelines VCEP 3.0, this variant is classified as a variant of uncertain significance. At least the following criteria are met: This variant has been identified as a de novo occurrence in an individual with CDKL5 disorder without confirmation of paternity and maternity (PM6, PMID: 18790821). This variant is absent from gnomAD (PM2_Supporting). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.040	T;T;T;.;.
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	.;D;D;D;D
M_CAP	Pathogenic	0.64	D
MetaRNN	Pathogenic	0.76	D;D;D;D;D
MetaSVM	Uncertain	0.23	D
MutationAssessor	Uncertain	2.0	M;.;M;.;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-0.77	N;.;N;.;.
REVEL	Uncertain	0.63
Sift	Pathogenic	0.0	D;.;D;.;.
Sift4G	Uncertain	0.0050	D;.;D;D;D
Polyphen		1.0	D;.;D;.;.
Vest4		0.43
MutPred		0.65		Gain of MoRF binding (P = 0.1104);Gain of MoRF binding (P = 0.1104);Gain of MoRF binding (P = 0.1104);Gain of MoRF binding (P = 0.1104);Gain of MoRF binding (P = 0.1104);
MVP		0.96
MPC		0.77
ClinPred		0.94	D
GERP RS		5.8
Varity_R		0.66
gMVP		0.35

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.32		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.32		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs267608653; hg19: chrX-18627690;