X-18564526-GATATATATATATAT-GATATAT

Variant names:

• chrX-18564526-GATATATAT-G
• rs745969938
• NM_001323289.2:c.145+21_145+28delATATATAT

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The ENST00000623535.2(CDKL5):​c.145+5_145+12delATATATAT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000363 in 606,181 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000011 (0 hom., 0 hem., cov: 19)
  • Exomes 𝑓: 0.000041 (0 hom. 1 hem.)
• Consequence: CDKL5 ENST00000623535.2 splice_region, intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• 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: Benign. The variant received -10 ACMG points.

• BP6: Variant X-18564526-GATATATAT-G is Benign according to our data. Variant chrX-18564526-GATATATAT-G is described in ClinVar as Likely_benign. ClinVar VariationId is 2928790.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAdExome4 allele frequency = 0.0000409 (21/512918) while in subpopulation EAS AF = 0.0000519 (1/19266). AF 95% confidence interval is 0.0000226. There are 0 homozygotes in GnomAdExome4. There are 1 alleles in the male GnomAdExome4 subpopulation. This position passed quality control check.
• BS2: High AC in GnomAdExome4 at 21 XL,AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000623535.2. 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+21_145+28delATATATAT		intron	N/A	NP_001310218.1	O76039-2
	CDKL5	NM_001037343.2		c.145+21_145+28delATATATAT		intron	N/A	NP_001032420.1	O76039-1
	CDKL5	NM_003159.3		c.145+21_145+28delATATATAT		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+12delATATATAT		splice_region intron	N/A	ENSP00000485244.1	O76039-2
	CDKL5	ENST00000379989.6	TSL:1	c.145+5_145+12delATATATAT		splice_region intron	N/A	ENSP00000369325.3	O76039-1
	CDKL5	ENST00000379996.7	TSL:1	c.145+5_145+12delATATATAT		splice_region intron	N/A	ENSP00000369332.3	O76039-1

Frequencies

GnomAD3 genomes AF: 0.0000107 AC: 1 AN: 93263 Hom.: 0 Cov.: 19

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000216

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000409 AC: 21 AN: 512918 Hom.: 0 AF XY: 0.00000798 AC XY: 1 AN XY: 125364

African (AFR) AF: 0.00 AC: 0 AN: 13388

American (AMR) AF: 0.00 AC: 0 AN: 24986

Ashkenazi Jewish (ASJ) AF: 0.0000819 AC: 1 AN: 12209

East Asian (EAS) AF: 0.0000519 AC: 1 AN: 19266

South Asian (SAS) AF: 0.0000343 AC: 1 AN: 29134

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 28771

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

European-Non Finnish (NFE) AF: 0.0000389 AC: 14 AN: 359539

Other (OTH) AF: 0.000169 AC: 4 AN: 23621

GnomAD4 genome AF: 0.0000107 AC: 1 AN: 93263 Hom.: 0 Cov.: 19 AF XY: 0.00 AC XY: 0 AN XY: 23405

African (AFR) AF: 0.00 AC: 0 AN: 25686

American (AMR) AF: 0.00 AC: 0 AN: 8314

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2323

East Asian (EAS) AF: 0.00 AC: 0 AN: 2968

South Asian (SAS) AF: 0.00 AC: 0 AN: 2063

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 3507

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 201

European-Non Finnish (NFE) AF: 0.0000216 AC: 1 AN: 46394

Other (OTH) AF: 0.00 AC: 0 AN: 1212

Alfa AF: 0.00 Hom.: 26

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Developmental and epileptic encephalopathy, 2;CN128785:Angelman syndrome-like (1)

Computational scores

Source: dbNSFP v4.9

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;