chrX-18564526-GATATATATATATAT-G

Variant names:

• chrX-18564526-GATATATATATATAT-G
• rs745969938
• NM_001323289.2:c.145+15_145+28delATATATATATATAT

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_001323289.2(CDKL5):​c.145+15_145+28delATATATATATATAT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000195 in 513,039 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 19)
  • Exomes 𝑓: 0.0000019 (0 hom. 0 hem.)
• Consequence: CDKL5 NM_001323289.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.26
• 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: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDKL5	NM_001323289.2	c.145+15_145+28delATATATATATATAT		intron_variant	Intron 4 of 17	ENST00000623535.2	NP_001310218.1
CDKL5	NM_001037343.2	c.145+15_145+28delATATATATATATAT		intron_variant	Intron 5 of 21		NP_001032420.1
CDKL5	NM_003159.3	c.145+15_145+28delATATATATATATAT		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+5_145+18delATATATATATATAT		splice_region_variant, intron_variant	Intron 4 of 17	1	NM_001323289.2	ENSP00000485244.1

Frequencies

GnomAD3 genomes Cov.: 19

GnomAD4 exome AF: 0.00000195 AC: 1 AN: 513039 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 125429

⚠️ 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: 13389

American (AMR) AF: 0.00 AC: 0 AN: 24992

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 12214

East Asian (EAS) AF: 0.00 AC: 0 AN: 19269

South Asian (SAS) AF: 0.00 AC: 0 AN: 29143

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 28779

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2004

European-Non Finnish (NFE) AF: 0.00000278 AC: 1 AN: 359626

Other (OTH) AF: 0.00 AC: 0 AN: 23623

⚠️ 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

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.3

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;