rs199814742

chrX-18564539-A-G

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.145+17A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00558 in 623,579 control chromosomes in the GnomAD database, including 30 homozygotes. There are 1,116 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 0.0036 (2 hom., 118 hem., cov: 21)
  • Exomes 𝑓: 0.0060 (28 hom. 998 hem.)
• Consequence: CDKL5 NM_001323289.2 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7 O:1
• Conservation: PhyloP100: -0.180

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=-0.91).
• BP6: Variant X-18564539-A-G is Benign according to our data. Variant chrX-18564539-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 136709.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-18564539-A-G is described in Lovd as [Benign]. Variant chrX-18564539-A-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00357 (381/106814) while in subpopulation NFE AF= 0.00448 (233/52042). AF 95% confidence interval is 0.00401. There are 2 homozygotes in gnomad4. There are 118 alleles in male gnomad4 subpopulation. Median coverage is 21. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDKL5	NM_001323289.2	c.145+17A>G		intron_variant		ENST00000623535.2
CDKL5	NM_001037343.2	c.145+17A>G		intron_variant
CDKL5	NM_003159.3	c.145+17A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDKL5	ENST00000623535.2	c.145+17A>G		intron_variant		1	NM_001323289.2	P1

Frequencies

GnomAD3 genomes AF: 0.00359 AC: 383 AN: 106819 Hom.: 2 Cov.: 21 AF XY: 0.00397 AC XY: 119 AN XY: 29959

Gnomad AFR AF: 0.000339

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00133

Gnomad ASJ AF: 0.0298

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00366

Gnomad FIN AF: 0.00430

Gnomad MID AF: 0.0429

Gnomad NFE AF: 0.00451

Gnomad OTH AF: 0.00561

GnomAD3 exomes AF: 0.00980 AC: 645 AN: 65810 Hom.: 11 AF XY: 0.0124 AC XY: 228 AN XY: 18352

Gnomad AFR exome AF: 0.00364

Gnomad AMR exome AF: 0.00570

Gnomad ASJ exome AF: 0.0419

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00392

Gnomad FIN exome AF: 0.00365

Gnomad NFE exome AF: 0.0118

Gnomad OTH exome AF: 0.0159

GnomAD4 exome AF: 0.00600 AC: 3101 AN: 516765 Hom.: 28 Cov.: 8 AF XY: 0.00888 AC XY: 998 AN XY: 112335

Gnomad4 AFR exome AF: 0.00153

Gnomad4 AMR exome AF: 0.00466

Gnomad4 ASJ exome AF: 0.0387

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00407

Gnomad4 FIN exome AF: 0.00534

Gnomad4 NFE exome AF: 0.00556

Gnomad4 OTH exome AF: 0.00725

GnomAD4 genome AF: 0.00357 AC: 381 AN: 106814 Hom.: 2 Cov.: 21 AF XY: 0.00394 AC XY: 118 AN XY: 29966

Gnomad4 AFR AF: 0.000339

Gnomad4 AMR AF: 0.00133

Gnomad4 ASJ AF: 0.0298

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00369

Gnomad4 FIN AF: 0.00430

Gnomad4 NFE AF: 0.00448

Gnomad4 OTH AF: 0.00555

Alfa AF: 0.00695 Hom.: 54

Bravo AF: 0.00322

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	curation	RettBASE	May 09, 2014	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 15, 2012	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 29, 2015	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Developmental and epileptic encephalopathy, 2 Benign:2

Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	May 03, 2022	- -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

not provided Other:1

not provided, flagged submission

literature only

RettBASE

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
Cadd	Benign	0.77
Dann	Benign	0.54

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: rs199814742; hg19: chrX-18582659;