X-18425831-T-C

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.-163+136T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0131 in 112,405 control chromosomes in the GnomAD database, including 12 homozygotes. There are 413 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 0.013 (12 hom., 411 hem., cov: 24)
  • Exomes 𝑓: 0.015 (0 hom. 2 hem.)
• Consequence: CDKL5 NM_001323289.2 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.262

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=-0.87).
• BP6: Variant X-18425831-T-C is Benign according to our data. Variant chrX-18425831-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 1189327.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0131 (1469/112271) while in subpopulation AFR AF= 0.0331 (1026/31002). AF 95% confidence interval is 0.0314. There are 12 homozygotes in gnomad4. There are 411 alleles in male gnomad4 subpopulation. Median coverage is 24. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 12 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDKL5	NM_001323289.2	c.-163+136T>C		intron_variant		ENST00000623535.2
CDKL5	NM_003159.3	c.-163+136T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDKL5	ENST00000623535.2	c.-163+136T>C		intron_variant		1	NM_001323289.2	P1
CDKL5	ENST00000379996.7	c.-163+136T>C		intron_variant		1
CDKL5	ENST00000674046.1	c.-163+136T>C		intron_variant

Frequencies

GnomAD3 genomes AF: 0.0131 AC: 1471 AN: 112229 Hom.: 12 Cov.: 24 AF XY: 0.0120 AC XY: 413 AN XY: 34517

Gnomad AFR AF: 0.0332

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00585

Gnomad ASJ AF: 0.0295

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00363

Gnomad FIN AF: 0.00368

Gnomad MID AF: 0.0460

Gnomad NFE AF: 0.00449

Gnomad OTH AF: 0.0145

GnomAD4 exome AF: 0.0149 AC: 2 AN: 134 Hom.: 0 AF XY: 0.0286 AC XY: 2 AN XY: 70

Gnomad4 AFR exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00840

Gnomad4 OTH exome AF: 0.143

GnomAD4 genome AF: 0.0131 AC: 1469 AN: 112271 Hom.: 12 Cov.: 24 AF XY: 0.0119 AC XY: 411 AN XY: 34569

Gnomad4 AFR AF: 0.0331

Gnomad4 AMR AF: 0.00584

Gnomad4 ASJ AF: 0.0295

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00364

Gnomad4 FIN AF: 0.00368

Gnomad4 NFE AF: 0.00446

Gnomad4 OTH AF: 0.0143

Alfa AF: 0.00936 Hom.: 38

Bravo AF: 0.0146

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

May 08, 2019

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
Cadd	Benign	7.3
Dann	Benign	0.49

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs187188170; hg19: chrX-18443951;