rs191864898

Variant names:

• chrX-18425467-G-T
• rs191864898
• NM_001323289.2:c.-391G>T

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.-391G>T variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00634 in 113,430 control chromosomes in the GnomAD database, including 7 homozygotes. There are 214 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 0.0063 (7 hom., 213 hem., cov: 24)
  • Exomes 𝑓: 0.0075 (0 hom. 1 hem.)
• Consequence: CDKL5 NM_001323289.2 upstream_gene
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.199

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-18425467-G-T is Benign according to our data. Variant chrX-18425467-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 158175.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00634 (718/113297) while in subpopulation NFE AF= 0.00997 (532/53351). AF 95% confidence interval is 0.00927. There are 7 homozygotes in gnomad4. There are 213 alleles in male gnomad4 subpopulation. Median coverage is 24. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 7 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDKL5	NM_001323289.2	c.-391G>T		upstream_gene_variant		ENST00000623535.2	NP_001310218.1
CDKL5	NM_003159.3	c.-391G>T		upstream_gene_variant			NP_003150.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDKL5	ENST00000623535.2	c.-391G>T		upstream_gene_variant		1	NM_001323289.2	ENSP00000485244.1
CDKL5	ENST00000379996.7	c.-391G>T		upstream_gene_variant		1		ENSP00000369332.3
CDKL5	ENST00000674046.1	c.-391G>T		upstream_gene_variant				ENSP00000501174.1

Frequencies

GnomAD3 genomes AF: 0.00634 AC: 718 AN: 113248 Hom.: 7 Cov.: 24 AF XY: 0.00602 AC XY: 213 AN XY: 35386

Gnomad AFR AF: 0.00131

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00600

Gnomad ASJ AF: 0.00789

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000355

Gnomad FIN AF: 0.00728

Gnomad MID AF: 0.00418

Gnomad NFE AF: 0.00997

Gnomad OTH AF: 0.00716

GnomAD4 exome AF: 0.00752 AC: 1 AN: 133 Hom.: 0 AF XY: 0.0133 AC XY: 1 AN XY: 75

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR 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: 0.00870

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00634 AC: 718 AN: 113297 Hom.: 7 Cov.: 24 AF XY: 0.00601 AC XY: 213 AN XY: 35445

Gnomad4 AFR AF: 0.00131

Gnomad4 AMR AF: 0.00599

Gnomad4 ASJ AF: 0.00789

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000356

Gnomad4 FIN AF: 0.00728

Gnomad4 NFE AF: 0.00997

Gnomad4 OTH AF: 0.00707

Alfa AF: 0.0107 Hom.: 59

Bravo AF: 0.00619

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

May 09, 2014

RettBASE

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: curation

Benign variation, found in normal male controls -

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

May 22, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

CDKL5 disorder Benign:1

Jun 28, 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 v3 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	6.6
DANN	Benign	0.87

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs191864898; hg19: chrX-18443587;