rs371902632

chrX-18625196-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_001323289.2(CDKL5):c.2445C>T(p.Ser815=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000424 in 1,204,226 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 14 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.00021 (0 hom., 6 hem., cov: 22)
  • Exomes 𝑓: 0.000026 (0 hom. 8 hem.)
• Consequence: CDKL5 NM_001323289.2 synonymous
• Clinical Significance: Benign reviewed by expert panel B:4
• Conservation: PhyloP100: 2.17

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.32).
• BP6: Variant X-18625196-C-T is Benign according to our data. Variant chrX-18625196-C-T is described in ClinVar as [Benign]. Clinvar id is 258978.Status of the report is reviewed_by_expert_panel, 3 stars.
• BP7: Synonymous conserved (PhyloP=2.17 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000209 (23/109938) while in subpopulation AFR AF= 0.000762 (23/30178). AF 95% confidence interval is 0.000521. There are 0 homozygotes in gnomad4. There are 6 alleles in male gnomad4 subpopulation. Median coverage is 22. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd at 6 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDKL5	NM_001323289.2	c.2445C>T	p.Ser815=	synonymous_variant	17/18	ENST00000623535.2
CDKL5	NM_001037343.2	c.2445C>T	p.Ser815=	synonymous_variant	18/22
CDKL5	NM_003159.3	c.2445C>T	p.Ser815=	synonymous_variant	17/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDKL5	ENST00000623535.2	c.2445C>T	p.Ser815=	synonymous_variant	17/18	1	NM_001323289.2	P1

Frequencies

GnomAD3 genomes AF: 0.000209 AC: 23 AN: 109884 Hom.: 0 Cov.: 22 AF XY: 0.000187 AC XY: 6 AN XY: 32106

Gnomad AFR AF: 0.000764

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: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000875 AC: 16 AN: 182778 Hom.: 0 AF XY: 0.0000595 AC XY: 4 AN XY: 67280

Gnomad AFR exome AF: 0.00114

Gnomad AMR exome AF: 0.0000365

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000256 AC: 28 AN: 1094288 Hom.: 0 Cov.: 30 AF XY: 0.0000222 AC XY: 8 AN XY: 359898

Gnomad4 AFR exome AF: 0.000911

Gnomad4 AMR exome AF: 0.0000568

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: 0.00

Gnomad4 OTH exome AF: 0.0000435

GnomAD4 genome AF: 0.000209 AC: 23 AN: 109938 Hom.: 0 Cov.: 22 AF XY: 0.000187 AC XY: 6 AN XY: 32170

Gnomad4 AFR AF: 0.000762

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: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000214 Hom.: 0

Bravo AF: 0.000314

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

CDKL5 disorder Benign:1

Benign, reviewed by expert panel

curation

ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel

Mar 26, 2021

The allele frequency of the p.Ser815= variant in CDKL5 is 0.1% in African sub population in gnomAD, which is high enough to be classified as benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BA1). The silent p.Ser815= variant is not predicted to affect splicing using multiple computational tools and does not affect a highly conserved nucleotide (BP7). In summary, the p.Ser815= variant in CDKL5 is classified as benign based on the ACMG/AMP criteria (BA1, BP7). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Oct 05, 2020

- -

Developmental and epileptic encephalopathy, 2;CN128785:Angelman syndrome-like Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 30, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.32
Cadd	Benign	8.3
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: rs371902632; hg19: chrX-18643316;