chrX-18609618-C-T

Variant names:

• chrX-18609618-C-T
• rs267608652
• NM_001323289.2:c.2152+48C>T

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.2152+48C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000466 in 1,202,397 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 12 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 0.000054 (0 hom., 2 hem., cov: 23)
  • Exomes 𝑓: 0.000046 (0 hom. 10 hem.)
• Consequence: CDKL5 NM_001323289.2 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:2 O:1
• Conservation: PhyloP100: -0.00500

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: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant X-18609618-C-T is Benign according to our data. Variant chrX-18609618-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 156078.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0000538 (6/111563) while in subpopulation NFE AF= 0.000113 (6/53130). AF 95% confidence interval is 0.0000485. There are 0 homozygotes in gnomad4. There are 2 alleles in male gnomad4 subpopulation. Median coverage is 23. 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.2152+48C>T		intron_variant	Intron 14 of 17	ENST00000623535.2	NP_001310218.1
CDKL5	NM_001037343.2	c.2152+48C>T		intron_variant	Intron 15 of 21		NP_001032420.1
CDKL5	NM_003159.3	c.2152+48C>T		intron_variant	Intron 14 of 20		NP_003150.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDKL5	ENST00000623535.2	c.2152+48C>T		intron_variant	Intron 14 of 17	1	NM_001323289.2	ENSP00000485244.1

Frequencies

GnomAD3 genomes AF: 0.0000538 AC: 6 AN: 111563 Hom.: 0 Cov.: 23 AF XY: 0.0000593 AC XY: 2 AN XY: 33719

Gnomad AFR AF: 0.00

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: 0.00

Gnomad NFE AF: 0.000113

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000469 AC: 8 AN: 170519 Hom.: 0 AF XY: 0.0000526 AC XY: 3 AN XY: 56985

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: 0.000108

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000458 AC: 50 AN: 1090834 Hom.: 0 Cov.: 31 AF XY: 0.0000280 AC XY: 10 AN XY: 357756

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.0000584

Gnomad4 OTH exome AF: 0.0000219

GnomAD4 genome AF: 0.0000538 AC: 6 AN: 111563 Hom.: 0 Cov.: 23 AF XY: 0.0000593 AC XY: 2 AN XY: 33719

Gnomad4 AFR AF: 0.00

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: 0.000113

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000216 Hom.: 2

Bravo AF: 0.0000529

ClinVar

Significance: Likely benign

Submissions summary: Benign:2 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Mar 13, 2014

RettBASE

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: curation

Unlikely to be pathogenic, not predicted to change splicing; however, there is no empirical evidence for this -

CDKL5 disorder Benign:1

Jul 11, 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 allele frequency of this variant in at least one population in gnomAD v3 is between 0.008% and 0.03% (BS1). 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	-0.92
CADD	Benign	2.8
DANN	Benign	0.69

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs267608652; hg19: chrX-18627738;