X-18564526-GATATATATATATAT-GATATATATATATATATATAT

Variant names:

• chrX-18564526-G-GATATAT
• rs745969938
• NM_001323289.2:c.145+23_145+28dupATATAT

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP6_Moderate

The NM_001323289.2(CDKL5):​c.145+23_145+28dupATATAT variant causes a intron change involving the alteration of a non-conserved nucleotide. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 19)
  • Exomes 𝑓: 0.000057 (0 hom. 0 hem.)
• Consequence: CDKL5 NM_001323289.2 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.405
• Publications: 0 publications found

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]

CDKL5 Gene-Disease associations (from GenCC):

• CDKL5 disorder

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
• developmental and epileptic encephalopathy, 2

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• atypical Rett syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• genetic developmental and epileptic encephalopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• infantile spasms

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• precocious puberty

  Inheritance: XL Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP6: Variant X-18564526-G-GATATAT is Benign according to our data. Variant chrX-18564526-G-GATATAT is described in ClinVar as Likely_benign. ClinVar VariationId is 1615526.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDKL5	NM_001323289.2	c.145+23_145+28dupATATAT		intron_variant	Intron 4 of 17	ENST00000623535.2	NP_001310218.1
CDKL5	NM_001037343.2	c.145+23_145+28dupATATAT		intron_variant	Intron 5 of 21		NP_001032420.1
CDKL5	NM_003159.3	c.145+23_145+28dupATATAT		intron_variant	Intron 4 of 20		NP_003150.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDKL5	ENST00000623535.2	c.145+4_145+5insATATAT		splice_region_variant, intron_variant	Intron 4 of 17	1	NM_001323289.2	ENSP00000485244.1

Frequencies

GnomAD3 genomes Cov.: 19

GnomAD4 exome AF: 0.0000566 AC: 29 AN: 512819 Hom.: 0 Cov.: 5 AF XY: 0.00 AC XY: 0 AN XY: 125309

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 13379

American (AMR) AF: 0.00 AC: 0 AN: 24984

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 12210

East Asian (EAS) AF: 0.000156 AC: 3 AN: 19251

South Asian (SAS) AF: 0.0000343 AC: 1 AN: 29127

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 28759

Middle Eastern (MID) AF: 0.000500 AC: 1 AN: 2001

European-Non Finnish (NFE) AF: 0.0000612 AC: 22 AN: 359492

Other (OTH) AF: 0.0000847 AC: 2 AN: 23616

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 19

Alfa AF: 0.00 Hom.: 26

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Jan 05, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.41
Mutation Taster		=100/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs745969938; hg19: chrX-18582646;