rs267608658

Variant names:

• chrX-18625097-T-C
• rs267608658
• NM_001323289.2:c.2377-31T>C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001323289.2(CDKL5):​c.2377-31T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000026 in 1,193,965 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 10 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.000036 (0 hom., 2 hem., cov: 22)
  • Exomes 𝑓: 0.000025 (0 hom. 8 hem.)
• Consequence: CDKL5 NM_001323289.2 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:2 O:1
• Conservation: PhyloP100: 0.417

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 -14 ACMG points.

• BP4: This position, referring to a specific DNA site, is a probable branch point but rather VUS (scored 5 / 10). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant X-18625097-T-C is Benign according to our data. Variant chrX-18625097-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 156083.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.0000249 (27/1083205) while in subpopulation NFE AF= 0.0000301 (25/829396). AF 95% confidence interval is 0.0000207. There are 0 homozygotes in gnomad4_exome. There are 8 alleles in male gnomad4_exome subpopulation. Median coverage is 27. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDKL5	NM_001323289.2	c.2377-31T>C		intron_variant	Intron 16 of 17	ENST00000623535.2	NP_001310218.1
CDKL5	NM_001037343.2	c.2377-31T>C		intron_variant	Intron 17 of 21		NP_001032420.1
CDKL5	NM_003159.3	c.2377-31T>C		intron_variant	Intron 16 of 20		NP_003150.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDKL5	ENST00000623535.2	c.2377-31T>C		intron_variant	Intron 16 of 17	1	NM_001323289.2	ENSP00000485244.1

Frequencies

GnomAD3 genomes AF: 0.0000361 AC: 4 AN: 110760 Hom.: 0 Cov.: 22 AF XY: 0.0000607 AC XY: 2 AN XY: 32928

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000962

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000567

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000548 AC: 1 AN: 182532 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 67154

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: 0.0000122

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000249 AC: 27 AN: 1083205 Hom.: 0 Cov.: 27 AF XY: 0.0000229 AC XY: 8 AN XY: 350071

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000284

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: 0.0000301

Gnomad4 OTH exome AF: 0.0000219

GnomAD4 genome AF: 0.0000361 AC: 4 AN: 110760 Hom.: 0 Cov.: 22 AF XY: 0.0000607 AC XY: 2 AN XY: 32928

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000962

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000567

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000302

ClinVar

Significance: Likely benign

Submissions summary: Benign:2 Other:1

Revision: criteria provided, single submitter

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

Sep 16, 2024

Centre for Population Genomics, CPG

Significance: Likely 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 likely benign. At least the following criteria are met: The variant is observed in at least 1 individual with no features of CDKL5 disorder (BS2_Supporting, PMID: 20397747). Synonymous or intronic variant outside donor and acceptor splice regions where splicing prediction algorithms do not support significant splicing alteration (spliceAI score <=0.1) (BP4, BP7). -

not provided Other:1

-

RettBASE

Significance: not provided

Review Status: flagged submission

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	4.8
DANN	Benign	0.67
BranchPoint Hunter		5.0

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: rs267608658; hg19: chrX-18643217;