rs786204954

Positions:

• chrX-18619898-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001323289.2(CDKL5):​c.2308C>A​(p.Gln770Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• 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: Uncertain significance criteria provided, single submitter U:1 B:1
• Conservation: PhyloP100: 4.42

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.28485432).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDKL5	NM_001323289.2	c.2308C>A	p.Gln770Lys	missense_variant	16/18	ENST00000623535.2	NP_001310218.1
CDKL5	NM_001037343.2	c.2308C>A	p.Gln770Lys	missense_variant	17/22		NP_001032420.1
CDKL5	NM_003159.3	c.2308C>A	p.Gln770Lys	missense_variant	16/21		NP_003150.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDKL5	ENST00000623535.2	c.2308C>A	p.Gln770Lys	missense_variant	16/18	1	NM_001323289.2	ENSP00000485244	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1084280 Hom.: 0 Cov.: 26 AF XY: 0.00 AC XY: 0 AN XY: 351372

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: Uncertain significance

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

CDKL5 disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

curation

Centre for Population Genomics, CPG

Jul 12, 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: The variant is observed in at least 1 individual with no features of CDKL5 disorder (BS2_Supporting). PMID: 23064044 met Computational prediction analysis tools suggest no impact on gene product (REVEL score <= 0.15) (BP4). This variant is absent from gnomAD v4 (PM2_Supporting). -

not specified Benign:1

Benign, no assertion criteria provided

curation

RettBASE

May 09, 2014

Inherited from unaffected mother, both proband and mother with random XCI; In silico prediction: SIFT = tolerated, MutationTaster = polymorphism, PolyPhen2 = benign, AlignGVGD = benign (C0) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.037	T;T;T;.;.
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.93	.;D;D;D;D
M_CAP	Pathogenic	0.69	D
MetaRNN	Benign	0.28	T;T;T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.7	L;.;L;.;L
MutationTaster	Benign	0.98	N;N
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-1.0	N;.;N;.;.
REVEL	Benign	0.092
Sift	Uncertain	0.022	D;.;D;.;.
Sift4G	Benign	0.081	T;.;T;T;T
Polyphen		0.43	B;.;B;.;.
Vest4		0.21
MutPred		0.11		Gain of ubiquitination at Q770 (P = 0.0117);Gain of ubiquitination at Q770 (P = 0.0117);Gain of ubiquitination at Q770 (P = 0.0117);Gain of ubiquitination at Q770 (P = 0.0117);Gain of ubiquitination at Q770 (P = 0.0117);
MVP		0.81
MPC		0.46
ClinPred		0.74	D
GERP RS		5.4
Varity_R		0.46
gMVP		0.23

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs786204954; hg19: chrX-18638018; COSMIC: COSV66111086;