rs146488512

chrX-18625217-C-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001323289.2(CDKL5):c.2466C>G(p.Arg822=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000121 in 1,206,133 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 36 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 0.00074 (0 hom., 20 hem., cov: 22)
  • Exomes 𝑓: 0.000059 (0 hom. 16 hem.)
• Consequence: CDKL5 NM_001323289.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.485

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant X-18625217-C-G is Benign according to our data. Variant chrX-18625217-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 258979.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.485 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000738 (81/109782) while in subpopulation AFR AF= 0.00258 (78/30175). AF 95% confidence interval is 0.00212. There are 0 homozygotes in gnomad4. There are 20 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd at 20 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDKL5	NM_001323289.2	c.2466C>G	p.Arg822=	synonymous_variant	17/18	ENST00000623535.2
CDKL5	NM_001037343.2	c.2466C>G	p.Arg822=	synonymous_variant	18/22
CDKL5	NM_003159.3	c.2466C>G	p.Arg822=	synonymous_variant	17/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDKL5	ENST00000623535.2	c.2466C>G	p.Arg822=	synonymous_variant	17/18	1	NM_001323289.2	P1

Frequencies

GnomAD3 genomes AF: 0.000738 AC: 81 AN: 109727 Hom.: 0 Cov.: 22 AF XY: 0.000626 AC XY: 20 AN XY: 31943

Gnomad AFR AF: 0.00259

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000981

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: 0.00137

GnomAD3 exomes AF: 0.000148 AC: 27 AN: 182661 Hom.: 0 AF XY: 0.0000298 AC XY: 2 AN XY: 67213

Gnomad AFR exome AF: 0.00190

Gnomad AMR exome AF: 0.0000729

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: 0.0000593 AC: 65 AN: 1096351 Hom.: 0 Cov.: 30 AF XY: 0.0000442 AC XY: 16 AN XY: 361915

Gnomad4 AFR exome AF: 0.00235

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: 0.0000217

GnomAD4 genome AF: 0.000738 AC: 81 AN: 109782 Hom.: 0 Cov.: 22 AF XY: 0.000625 AC XY: 20 AN XY: 32008

Gnomad4 AFR AF: 0.00258

Gnomad4 AMR AF: 0.0000980

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: 0.00135

Alfa AF: 0.000260 Hom.: 1

Bravo AF: 0.000718

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 24, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
Cadd	Benign	1.3
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: rs146488512; hg19: chrX-18643337;