X-18579749-C-A

Variant names:

• chrX-18579749-C-A
• rs4825261
• NM_001323289.2:c.283-99C>A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001323289.2(CDKL5):​c.283-99C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.314 in 781,995 control chromosomes in the GnomAD database, including 28,867 homozygotes. There are 71,175 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.28 (3433 hom., 9251 hem., cov: 23)
  • Exomes 𝑓: 0.32 (25434 hom. 61924 hem.)
• Consequence: CDKL5 NM_001323289.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4 O:1
• Conservation: PhyloP100: -0.739

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant X-18579749-C-A is Benign according to our data. Variant chrX-18579749-C-A is described in ClinVar as [Benign]. Clinvar id is 156085.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.439 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDKL5	NM_001323289.2	c.283-99C>A		intron_variant	Intron 5 of 17	ENST00000623535.2	NP_001310218.1
CDKL5	NM_001037343.2	c.283-99C>A		intron_variant	Intron 6 of 21		NP_001032420.1
CDKL5	NM_003159.3	c.283-99C>A		intron_variant	Intron 5 of 20		NP_003150.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDKL5	ENST00000623535.2	c.283-99C>A		intron_variant	Intron 5 of 17	1	NM_001323289.2	ENSP00000485244.1

Frequencies

GnomAD3 genomes AF: 0.283 AC: 31182 AN: 110051 Hom.: 3437 Cov.: 23 AF XY: 0.285 AC XY: 9237 AN XY: 32391

Gnomad AFR AF: 0.165

Gnomad AMI AF: 0.266

Gnomad AMR AF: 0.425

Gnomad ASJ AF: 0.410

Gnomad EAS AF: 0.459

Gnomad SAS AF: 0.411

Gnomad FIN AF: 0.260

Gnomad MID AF: 0.285

Gnomad NFE AF: 0.302

Gnomad OTH AF: 0.283

GnomAD4 exome AF: 0.319 AC: 214153 AN: 671895 Hom.: 25434 AF XY: 0.337 AC XY: 61924 AN XY: 183723

Gnomad4 AFR exome AF: 0.152

Gnomad4 AMR exome AF: 0.523

Gnomad4 ASJ exome AF: 0.392

Gnomad4 EAS exome AF: 0.465

Gnomad4 SAS exome AF: 0.413

Gnomad4 FIN exome AF: 0.270

Gnomad4 NFE exome AF: 0.298

Gnomad4 OTH exome AF: 0.315

GnomAD4 genome AF: 0.283 AC: 31182 AN: 110100 Hom.: 3433 Cov.: 23 AF XY: 0.285 AC XY: 9251 AN XY: 32450

Gnomad4 AFR AF: 0.165

Gnomad4 AMR AF: 0.426

Gnomad4 ASJ AF: 0.410

Gnomad4 EAS AF: 0.458

Gnomad4 SAS AF: 0.414

Gnomad4 FIN AF: 0.260

Gnomad4 NFE AF: 0.302

Gnomad4 OTH AF: 0.283

Alfa AF: 0.168 Hom.: 897

Bravo AF: 0.298

ClinVar

Significance: Benign

Submissions summary: Benign:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2 Other:1

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
not provided, flagged submission	literature only	RettBASE	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 14, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not specified Benign:1

Benign, no assertion criteria provided

curation

RettBASE

Mar 13, 2014

Common SNP -

CDKL5 disorder Benign:1

Benign, 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 benign. At least the following criteria are met: The allele frequency of this variant in at least one population in gnomAD v4 is higher than the 0.03% threshold defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like Disorders VCEP 3.0 (BA1). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.074
DANN	Benign	0.56

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: rs4825261; hg19: chrX-18597869; COSMIC: COSV66110067; COSMIC: COSV66110067;