X-18625241-G-C

Variant names:

• chrX-18625241-G-C
• rs1485485459
• NM_001323289.2:c.2490G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001323289.2(CDKL5):​c.2490G>C​(p.Gln830His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000913 in 109,551 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.0000091 (0 hom., 1 hem., cov: 21)
• Consequence: CDKL5 NM_001323289.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.29
• Publications: 0 publications found

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]

CDKL5 Gene-Disease associations (from GenCC):

• CDKL5 disorder

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
• developmental and epileptic encephalopathy, 2

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• atypical Rett syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• genetic developmental and epileptic encephalopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• infantile spasms

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• precocious puberty

  Inheritance: XL Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12868643).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001323289.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDKL5	NM_001323289.2	MANE Select	c.2490G>C	p.Gln830His	missense	Exon 17 of 18	NP_001310218.1
	CDKL5	NM_001037343.2		c.2490G>C	p.Gln830His	missense	Exon 18 of 22	NP_001032420.1
	CDKL5	NM_003159.3		c.2490G>C	p.Gln830His	missense	Exon 17 of 21	NP_003150.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDKL5	ENST00000623535.2	TSL:1 MANE Select	c.2490G>C	p.Gln830His	missense	Exon 17 of 18	ENSP00000485244.1
	CDKL5	ENST00000379989.6	TSL:1	c.2490G>C	p.Gln830His	missense	Exon 18 of 22	ENSP00000369325.3
	CDKL5	ENST00000379996.7	TSL:1	c.2490G>C	p.Gln830His	missense	Exon 17 of 21	ENSP00000369332.3

Frequencies

GnomAD3 genomes AF: 0.00000913 AC: 1 AN: 109551 Hom.: 0 Cov.: 21

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000190

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome AF: 0.00000913 AC: 1 AN: 109551 Hom.: 0 Cov.: 21 AF XY: 0.0000314 AC XY: 1 AN XY: 31831

African (AFR) AF: 0.00 AC: 0 AN: 30022

American (AMR) AF: 0.00 AC: 0 AN: 10182

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2622

East Asian (EAS) AF: 0.00 AC: 0 AN: 3511

South Asian (SAS) AF: 0.00 AC: 0 AN: 2433

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5793

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 240

European-Non Finnish (NFE) AF: 0.0000190 AC: 1 AN: 52619

Other (OTH) AF: 0.00 AC: 0 AN: 1451

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Developmental and epileptic encephalopathy, 2;CN128785:Angelman syndrome-like Uncertain:1

Oct 25, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This sequence change replaces glutamine with histidine at codon 830 of the CDKL5 protein (p.Gln830His). The glutamine residue is highly conserved and there is a small physicochemical difference between glutamine and histidine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with CDKL5-related disease. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.070	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	12
DANN	Benign	0.95
DEOGEN2	Benign	0.022	T
FATHMM_MKL	Benign	0.63	D
LIST_S2	Benign	0.16	T
M_CAP	Pathogenic	0.39	D
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.1	L
PhyloP100		1.3
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.17	N
REVEL	Benign	0.26
Sift	Benign	0.069	T
Sift4G	Benign	0.45	T
Polyphen		0.016	B
Vest4		0.32
MutPred		0.046		Loss of MoRF binding (P = 0.1185)
MVP		0.91
MPC		0.45
ClinPred		0.13	T
GERP RS		1.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.15
gMVP		0.31
Mutation Taster		=95/5	polymorphism

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

Other links and lift over

dbSNP: rs1485485459; hg19: chrX-18643361;