X-18579749-C-A

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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

Our verdict: Benign. The variant received -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

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 AC: 2601 AN: 17061

Gnomad4 AMR exome AF: 0.523 AC: 14547 AN: 27820

Gnomad4 ASJ exome AF: 0.392 AC: 6007 AN: 15323

Gnomad4 EAS exome AF: 0.465 AC: 12650 AN: 27215

Gnomad4 SAS exome AF: 0.413 AC: 16360 AN: 39630

Gnomad4 FIN exome AF: 0.270 AC: 10155 AN: 37625

Gnomad4 NFE exome AF: 0.298 AC: 141111 AN: 473233

Gnomad4 Remaining exome AF: 0.315 AC: 9806 AN: 31175

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 AC: 0.164878 AN: 0.164878

Gnomad4 AMR AF: 0.426 AC: 0.425649 AN: 0.425649

Gnomad4 ASJ AF: 0.410 AC: 0.410354 AN: 0.410354

Gnomad4 EAS AF: 0.458 AC: 0.458213 AN: 0.458213

Gnomad4 SAS AF: 0.414 AC: 0.413583 AN: 0.413583

Gnomad4 FIN AF: 0.260 AC: 0.259954 AN: 0.259954

Gnomad4 NFE AF: 0.302 AC: 0.30223 AN: 0.30223

Gnomad4 OTH AF: 0.283 AC: 0.282565 AN: 0.282565

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

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

-

RettBASE

Significance: not provided

Review Status: flagged submission

Collection Method: literature only

- -

not specified Benign:1

Mar 13, 2014

RettBASE

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: curation

Common SNP -

CDKL5 disorder Benign:1

Jul 12, 2024

Centre for Population Genomics, CPG

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

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
Mutation Taster		=100/0	polymorphism (auto)

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;