X-18425834-C-CTT

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_001323289.2(CDKL5):c.-163+139_-163+140insTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00314 in 112,888 control chromosomes in the GnomAD database, including 1 homozygotes. There are 130 hemizygotes in GnomAD. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: 𝑓 0.0031 (1 hom., 130 hem., cov: 24)
• Consequence: CDKL5 NM_001323289.2 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.296

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.

• BP6: Variant X-18425834-C-CTT is Benign according to our data. Variant chrX-18425834-C-CTT is described in ClinVar as [Likely_benign]. Clinvar id is 1194507.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00314 (354/112888) while in subpopulation NFE AF= 0.00393 (209/53134). AF 95% confidence interval is 0.0035. There are 1 homozygotes in gnomad4. There are 130 alleles in male gnomad4 subpopulation. Median coverage is 24. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd at 130 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDKL5	NM_001323289.2	c.-163+139_-163+140insTT		intron_variant		ENST00000623535.2
CDKL5	NM_003159.3	c.-163+139_-163+140insTT		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDKL5	ENST00000623535.2	c.-163+139_-163+140insTT		intron_variant		1	NM_001323289.2	P1
CDKL5	ENST00000379996.7	c.-163+139_-163+140insTT		intron_variant		1
CDKL5	ENST00000674046.1	c.-163+139_-163+140insTT		intron_variant

Frequencies

GnomAD3 genomes AF: 0.00314 AC: 354 AN: 112840 Hom.: 1 Cov.: 24 AF XY: 0.00371 AC XY: 130 AN XY: 35014

Gnomad AFR AF: 0.000578

Gnomad AMI AF: 0.0222

Gnomad AMR AF: 0.00212

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0135

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00393

Gnomad OTH AF: 0.00261

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.00314 AC: 354 AN: 112888 Hom.: 1 Cov.: 24 AF XY: 0.00371 AC XY: 130 AN XY: 35072

Gnomad4 AFR AF: 0.000577

Gnomad4 AMR AF: 0.00212

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0135

Gnomad4 NFE AF: 0.00393

Gnomad4 OTH AF: 0.00258

Alfa AF: 0.00828 Hom.: 8

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

Sep 20, 2019

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Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1401710048; hg19: chrX-18443954;