X-18442160-A-G

Position:

• chrX-18442160-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001323289.2(CDKL5):​c.-163+16465A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0269 in 110,730 control chromosomes in the GnomAD database, including 89 homozygotes. There are 922 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.027 (88 hom., 922 hem., cov: 22)
  • Exomes 𝑓: 0.034 (1 hom. 0 hem.)
• Consequence: CDKL5 NM_001323289.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.33

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=-0.9).
• BP6: Variant X-18442160-A-G is Benign according to our data. Variant chrX-18442160-A-G is described in ClinVar as [Benign]. Clinvar id is 1222003.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.177 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDKL5	NM_001323289.2	c.-163+16465A>G		intron_variant		ENST00000623535.2	NP_001310218.1
CDKL5	NM_003159.3	c.-163+16465A>G		intron_variant			NP_003150.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDKL5	ENST00000623535.2	c.-163+16465A>G		intron_variant		1	NM_001323289.2	ENSP00000485244.1

Frequencies

GnomAD3 genomes AF: 0.0267 AC: 2956 AN: 110619 Hom.: 88 Cov.: 22 AF XY: 0.0277 AC XY: 912 AN XY: 32921

Gnomad AFR AF: 0.0611

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0210

Gnomad ASJ AF: 0.000379

Gnomad EAS AF: 0.188

Gnomad SAS AF: 0.0641

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00424

Gnomad NFE AF: 0.000435

Gnomad OTH AF: 0.0295

GnomAD4 exome AF: 0.0339 AC: 2 AN: 59 Hom.: 1 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 27

Gnomad4 AFR exome AF: 0.667

Gnomad4 AMR 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: 0.00

GnomAD4 genome AF: 0.0269 AC: 2972 AN: 110671 Hom.: 88 Cov.: 22 AF XY: 0.0280 AC XY: 922 AN XY: 32983

Gnomad4 AFR AF: 0.0614

Gnomad4 AMR AF: 0.0210

Gnomad4 ASJ AF: 0.000379

Gnomad4 EAS AF: 0.189

Gnomad4 SAS AF: 0.0636

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000435

Gnomad4 OTH AF: 0.0304

Alfa AF: 0.0266 Hom.: 65

Bravo AF: 0.0329

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 31, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.41
DANN	Benign	0.62

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs2283722; hg19: chrX-18460280;