rs137874941

Variant names:

• chrX-18510888-A-G
• rs137874941
• NM_001323289.2:c.99+34A>G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001323289.2(CDKL5):​c.99+34A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000177 in 1,035,356 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 45 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00063 (0 hom., 16 hem., cov: 23)
  • Exomes 𝑓: 0.00012 (0 hom. 29 hem.)
• Consequence: CDKL5 NM_001323289.2 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -2.90

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=-0.9).
• BP6: Variant X-18510888-A-G is Benign according to our data. Variant chrX-18510888-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 189542.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000635 (71/111831) while in subpopulation AFR AF= 0.00217 (67/30858). AF 95% confidence interval is 0.00175. There are 0 homozygotes in gnomad4. There are 16 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd4 at 16 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDKL5	NM_001323289.2	c.99+34A>G		intron_variant	Intron 3 of 17	ENST00000623535.2	NP_001310218.1
CDKL5	NM_001037343.2	c.99+34A>G		intron_variant	Intron 4 of 21		NP_001032420.1
CDKL5	NM_003159.3	c.99+34A>G		intron_variant	Intron 3 of 20		NP_003150.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDKL5	ENST00000623535.2	c.99+34A>G		intron_variant	Intron 3 of 17	1	NM_001323289.2	ENSP00000485244.1

Frequencies

GnomAD3 genomes AF: 0.000635 AC: 71 AN: 111780 Hom.: 0 Cov.: 23 AF XY: 0.000471 AC XY: 16 AN XY: 33946

Gnomad AFR AF: 0.00218

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: 0.00417

Gnomad NFE AF: 0.0000564

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000223 AC: 40 AN: 179288 Hom.: 0 AF XY: 0.0000921 AC XY: 6 AN XY: 65140

Gnomad AFR exome AF: 0.00240

Gnomad AMR exome AF: 0.000184

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: 0.0000495

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000121 AC: 112 AN: 923525 Hom.: 0 Cov.: 17 AF XY: 0.000113 AC XY: 29 AN XY: 256623

Gnomad4 AFR exome AF: 0.00224

Gnomad4 AMR exome AF: 0.000172

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: 0.0000714

Gnomad4 OTH exome AF: 0.000124

GnomAD4 genome AF: 0.000635 AC: 71 AN: 111831 Hom.: 0 Cov.: 23 AF XY: 0.000470 AC XY: 16 AN XY: 34007

Gnomad4 AFR AF: 0.00217

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000564

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000476 Hom.: 1

Bravo AF: 0.000695

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

May 09, 2014

RettBASE

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: curation

- -

CDKL5 disorder Benign:1

Jul 11, 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: met The allele frequency of this variant in at least one population in gnomAD 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). -

not provided Benign:1

Jan 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CDKL5: BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.043
DANN	Benign	0.65

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: rs137874941; hg19: chrX-18529008;