chrX-18564526-GATATAT-G

Variant names:

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

Variant summary

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

The ENST00000623535.2(CDKL5):​c.145+5_145+10delATATAT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00037 in 604,996 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. 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: 𝑓 0.000011 (0 hom., 0 hem., cov: 19)
  • Exomes 𝑓: 0.00044 (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: Likely_benign. The variant received -2 ACMG points.

• BP6: Variant X-18564526-GATATAT-G is Benign according to our data. Variant chrX-18564526-GATATAT-G is described in ClinVar as Likely_benign. ClinVar VariationId is 3754381.Status of the report is criteria_provided_single_submitter, 1 stars.

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+23_145+28delATATAT		intron	N/A	NP_001310218.1	O76039-2
	CDKL5	NM_001037343.2		c.145+23_145+28delATATAT		intron	N/A	NP_001032420.1	O76039-1
	CDKL5	NM_003159.3		c.145+23_145+28delATATAT		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+10delATATAT		splice_region intron	N/A	ENSP00000485244.1	O76039-2
	CDKL5	ENST00000379989.6	TSL:1	c.145+5_145+10delATATAT		splice_region intron	N/A	ENSP00000369325.3	O76039-1
	CDKL5	ENST00000379996.7	TSL:1	c.145+5_145+10delATATAT		splice_region intron	N/A	ENSP00000369332.3	O76039-1

Frequencies

GnomAD3 genomes AF: 0.0000107 AC: 1 AN: 93260 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: 0.000285

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000261 AC: 19 AN: 72668 AF XY: 0.00

Gnomad AFR exome AF: 0.000526

Gnomad AMR exome AF: 0.000233

Gnomad ASJ exome AF: 0.000300

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000163

Gnomad NFE exome AF: 0.000321

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000436 AC: 223 AN: 511736 Hom.: 0 AF XY: 0.00000801 AC XY: 1 AN XY: 124870

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

African (AFR) AF: 0.000449 AC: 6 AN: 13370

American (AMR) AF: 0.000321 AC: 8 AN: 24943

Ashkenazi Jewish (ASJ) AF: 0.000411 AC: 5 AN: 12176

East Asian (EAS) AF: 0.000782 AC: 15 AN: 19182

South Asian (SAS) AF: 0.000103 AC: 3 AN: 29075

European-Finnish (FIN) AF: 0.000384 AC: 11 AN: 28668

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2001

European-Non Finnish (NFE) AF: 0.000463 AC: 166 AN: 358784

Other (OTH) AF: 0.000382 AC: 9 AN: 23537

⚠️ 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 AF: 0.0000107 AC: 1 AN: 93260 Hom.: 0 Cov.: 19 AF XY: 0.00 AC XY: 0 AN XY: 23404

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

African (AFR) AF: 0.00 AC: 0 AN: 25685

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: 0.000285 AC: 1 AN: 3505

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 46394

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

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

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
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;