rs374030184

chrX-18584254-A-G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_001323289.2(CDKL5):c.464-9A>G variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000747 in 1,164,119 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 26 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00013 (0 hom., 5 hem., cov: 23)
  • Exomes 𝑓: 0.000069 (0 hom. 21 hem.)
• Consequence: CDKL5 NM_001323289.2 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.000006842
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.911

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant X-18584254-A-G is Benign according to our data. Variant chrX-18584254-A-G is described in ClinVar as [Benign]. Clinvar id is 533399.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-18584254-A-G is described in Lovd as [Likely_benign].
• BS2: High Hemizygotes in GnomAd at 5 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDKL5	NM_001323289.2	c.464-9A>G		splice_polypyrimidine_tract_variant, intron_variant		ENST00000623535.2
CDKL5	NM_001037343.2	c.464-9A>G		splice_polypyrimidine_tract_variant, intron_variant
CDKL5	NM_003159.3	c.464-9A>G		splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDKL5	ENST00000623535.2	c.464-9A>G		splice_polypyrimidine_tract_variant, intron_variant		1	NM_001323289.2	P1

Frequencies

GnomAD3 genomes AF: 0.000125 AC: 14 AN: 111945 Hom.: 0 Cov.: 23 AF XY: 0.000147 AC XY: 5 AN XY: 34123

Gnomad AFR AF: 0.000162

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: 0.000169

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000983 AC: 18 AN: 183096 Hom.: 0 AF XY: 0.000118 AC XY: 8 AN XY: 67688

Gnomad AFR exome AF: 0.000228

Gnomad AMR exome AF: 0.0000365

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000524

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000159

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000694 AC: 73 AN: 1052174 Hom.: 0 Cov.: 25 AF XY: 0.0000641 AC XY: 21 AN XY: 327536

Gnomad4 AFR exome AF: 0.0000783

Gnomad4 AMR exome AF: 0.0000285

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000666

Gnomad4 SAS exome AF: 0.0000565

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000762

Gnomad4 OTH exome AF: 0.0000674

GnomAD4 genome AF: 0.000125 AC: 14 AN: 111945 Hom.: 0 Cov.: 23 AF XY: 0.000147 AC XY: 5 AN XY: 34123

Gnomad4 AFR AF: 0.000162

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: 0.000169

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000182 Hom.: 2

Bravo AF: 0.000166

EpiCase AF: 0.000218

EpiControl AF: 0.000475

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 15, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
Cadd	Benign	0.0090
Dann	Benign	0.49

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0000068
dbscSNV1_RF	Benign	0.0060
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: rs374030184; hg19: chrX-18602374;