X-18604324-A-G

Position:

• chrX-18604324-A-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4 BP6_Very_Strong

The NM_001323289.2(CDKL5):​c.1400A>G​(p.His467Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000109 in 1,097,196 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. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H467P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.000011 (0 hom. 1 hem.)
• Consequence: CDKL5 NM_001323289.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 7.01

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 Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.40388528).
• BP6: Variant X-18604324-A-G is Benign according to our data. Variant chrX-18604324-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 158178.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDKL5	NM_001323289.2	c.1400A>G	p.His467Arg	missense_variant	12/18	ENST00000623535.2
CDKL5	NM_001037343.2	c.1400A>G	p.His467Arg	missense_variant	13/22
CDKL5	NM_003159.3	c.1400A>G	p.His467Arg	missense_variant	12/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDKL5	ENST00000623535.2	c.1400A>G	p.His467Arg	missense_variant	12/18	1	NM_001323289.2	P1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD3 exomes AF: 0.00000548 AC: 1 AN: 182529 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 67267

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000123

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000109 AC: 12 AN: 1097196 Hom.: 0 Cov.: 32 AF XY: 0.00000276 AC XY: 1 AN XY: 362654

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: 0.0000185

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000131

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 22

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Likely benign, no assertion criteria provided	curation	RettBASE	May 09, 2014	Likely benign variation, found in normal female carrier; reported as c.1399A>G, but should be c.1400A>G; in silico predictions: SIFT = deleterious, MutationTaster = disease-causing, PolyPhen2 = probably damaging, AlignGVGD = C25 -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -

Developmental and epileptic encephalopathy, 2 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Aug 28, 2019

A heterozygous missense variant, NM_003159.2(CDKL5):c.1400A>G, has been identified in exon 12 of 21 of the CDKL5 gene. The variant is predicted to result in a minor amino acid change from His to Arg at position 467 of the protein (NP_003150.1(CDKL5):p.(His467Arg)). The His residue at this position has high conservation (100 vertebrates, UCSC), but is not located within a well established functional domain. In-silico predictions for this variant are consistently pathogenic (Polyphen, SIFT, CADD, Mutation Taster). The variant is present in the gnomAD database at a frequency of 0.0005% (1 heterozyogte, 0 homozygotes, 0 hemizygoutes). The variant has been previously described as benign and segregated with disease in one family with disease (ClinVar, RettBASE, Evans et al 2005)). A different variant in the same codon resulting in a change to proline has also been reported as VUS (ClinVar, RettBASE, Liang et al 2011)). Based on the information available at the time of curation, this variant has been classified as LIKELY BENIGN. -

CDKL5 disorder Benign:1

Likely benign, criteria provided, single submitter

curation

Centre for Population Genomics, CPG

Jul 01, 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 likely benign. At least the following criteria are met: This variant is present in 11 heterozygous and 1 hemizygous in gnomAD v4 . The variant is observed in at least 2 individuals with no features of CDKL5 disorder (BS2). PMID: 16015284 -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Apr 01, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.63
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.040
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.20	T;T;.;T;.;.
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.87	.;D;D;D;D;D
M_CAP	Pathogenic	0.58	D
MetaRNN	Benign	0.40	T;T;T;T;T;T
MetaSVM	Uncertain	-0.13	T
MutationAssessor	Benign	1.9	M;.;.;M;.;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-3.0	D;.;.;D;.;.
REVEL	Uncertain	0.40
Sift	Uncertain	0.0010	D;.;.;D;.;.
Sift4G	Benign	0.069	T;.;.;T;T;T
Polyphen		1.0	D;.;.;D;.;.
Vest4		0.72
MutPred		0.27		Gain of MoRF binding (P = 0.008);Gain of MoRF binding (P = 0.008);Gain of MoRF binding (P = 0.008);Gain of MoRF binding (P = 0.008);Gain of MoRF binding (P = 0.008);Gain of MoRF binding (P = 0.008);
MVP		0.88
MPC		0.57
ClinPred		0.45	T
GERP RS		6.1
Varity_R		0.73
gMVP		0.42

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: rs267608631; hg19: chrX-18622444;