chrX-18564526-G-GAT

Position:

• chrX-18564526-G-GAT

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The ENST00000623535.2(CDKL5):​c.145+4_145+5insAT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (4 hom., 177 hem., cov: 19)
  • Exomes 𝑓: 0.061 (0 hom. 55 hem.)
• Consequence: CDKL5 ENST00000623535.2 splice_region, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.405

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 -16 ACMG points.

• BP6: Variant X-18564526-G-GAT is Benign according to our data. Variant chrX-18564526-G-GAT is described in ClinVar as [Benign]. Clinvar id is 414804.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0642 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDKL5	NM_001323289.2	c.145+27_145+28dupAT		intron_variant		ENST00000623535.2	NP_001310218.1
CDKL5	NM_001037343.2	c.145+27_145+28dupAT		intron_variant			NP_001032420.1
CDKL5	NM_003159.3	c.145+27_145+28dupAT		intron_variant			NP_003150.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDKL5	ENST00000623535.2	c.145+4_145+5insAT		splice_region_variant, intron_variant		1	NM_001323289.2	ENSP00000485244.1

Frequencies

GnomAD3 genomes AF: 0.0123 AC: 1140 AN: 93017 Hom.: 4 Cov.: 19 AF XY: 0.00763 AC XY: 178 AN XY: 23319

Gnomad AFR AF: 0.0146

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0159

Gnomad ASJ AF: 0.00388

Gnomad EAS AF: 0.0159

Gnomad SAS AF: 0.0204

Gnomad FIN AF: 0.00949

Gnomad MID AF: 0.00498

Gnomad NFE AF: 0.0103

Gnomad OTH AF: 0.0190

GnomAD3 exomes AF: 0.0517 AC: 3755 AN: 72668 Hom.: 0 AF XY: 0.000463 AC XY: 5 AN XY: 10808

Gnomad AFR exome AF: 0.0103

Gnomad AMR exome AF: 0.0266

Gnomad ASJ exome AF: 0.0937

Gnomad EAS exome AF: 0.0224

Gnomad SAS exome AF: 0.0833

Gnomad FIN exome AF: 0.118

Gnomad NFE exome AF: 0.0519

Gnomad OTH exome AF: 0.0453

GnomAD4 exome AF: 0.0609 AC: 28132 AN: 461766 Hom.: 0 Cov.: 5 AF XY: 0.000591 AC XY: 55 AN XY: 93086

Gnomad4 AFR exome AF: 0.0545

Gnomad4 AMR exome AF: 0.0311

Gnomad4 ASJ exome AF: 0.0637

Gnomad4 EAS exome AF: 0.0627

Gnomad4 SAS exome AF: 0.0346

Gnomad4 FIN exome AF: 0.0655

Gnomad4 NFE exome AF: 0.0649

Gnomad4 OTH exome AF: 0.0618

GnomAD4 genome AF: 0.0122 AC: 1138 AN: 92992 Hom.: 4 Cov.: 19 AF XY: 0.00759 AC XY: 177 AN XY: 23320

Gnomad4 AFR AF: 0.0146

Gnomad4 AMR AF: 0.0158

Gnomad4 ASJ AF: 0.00388

Gnomad4 EAS AF: 0.0159

Gnomad4 SAS AF: 0.0206

Gnomad4 FIN AF: 0.00949

Gnomad4 NFE AF: 0.0103

Gnomad4 OTH AF: 0.0189

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 21, 2019

- -

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

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: rs745969938; hg19: chrX-18582646;