NM_001323289.2:c.145+19_145+28delATATATATAT

Variant names:

• chrX-18564526-GATATATATAT-G
• rs745969938
• NM_001323289.2:c.145+19_145+28delATATATATAT

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001323289.2(CDKL5):​c.145+19_145+28delATATATATAT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000039 in 513,013 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 19)
  • Exomes 𝑓: 0.0000039 (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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001323289.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDKL5	NM_001323289.2	MANE Select	c.145+19_145+28delATATATATAT		intron	N/A	NP_001310218.1	O76039-2
	CDKL5	NM_001037343.2		c.145+19_145+28delATATATATAT		intron	N/A	NP_001032420.1	O76039-1
	CDKL5	NM_003159.3		c.145+19_145+28delATATATATAT		intron	N/A	NP_003150.1	O76039-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDKL5	ENST00000623535.2	TSL:1 MANE Select	c.145+5_145+14delATATATATAT		splice_region intron	N/A	ENSP00000485244.1	O76039-2
	CDKL5	ENST00000379989.6	TSL:1	c.145+5_145+14delATATATATAT		splice_region intron	N/A	ENSP00000369325.3	O76039-1
	CDKL5	ENST00000379996.7	TSL:1	c.145+5_145+14delATATATATAT		splice_region intron	N/A	ENSP00000369332.3	O76039-1

Frequencies

GnomAD3 genomes Cov.: 19

GnomAD4 exome AF: 0.00000390 AC: 2 AN: 513013 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 125421

⚠️ 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: 12213

East Asian (EAS) AF: 0.00 AC: 0 AN: 19267

South Asian (SAS) AF: 0.00 AC: 0 AN: 29140

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 28778

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

European-Non Finnish (NFE) AF: 0.00000556 AC: 2 AN: 359609

Other (OTH) AF: 0.00 AC: 0 AN: 23621

⚠️ 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 v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.3
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;