chrX-18604374-ACCAAGG-A

Variant names:

• chrX-18604374-ACCAAGG-A
• rs587783114
• NM_001323289.2:c.1455_1460delGGCCAA

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BS2_Supporting BA1

This summary comes from the ClinGen Evidence Repository: The allele frequency of the p.Ala486_Lys487del variant in CDKL5 is 0.03% in Latino/Admixed American sub population in gnomAD, which is high enough to be classified as benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BA1). The p.Ala486_Lys487del variant is observed in 1 unaffected individual (RettBASE, PMID 22867051) (BS2_supporting). In summary, the p.Ala486_Lys487del variant in CDKL5 is classified as benign based on the ACMG/AMP criteria applied (BA1, BS2_supporting). LINK:https://erepo.genome.network/evrepo/ui/classification/CA199357/MONDO:0100039/016

• Frequency:
  • Genomes: 𝑓 0.000027 (0 hom., 2 hem., cov: 22)
  • Exomes 𝑓: 0.000098 (0 hom. 41 hem.)
• Consequence: CDKL5 NM_001323289.2 disruptive_inframe_deletion
• Clinical Significance: Benign reviewed by expert panel U:1 B:5
• Conservation: PhyloP100: 6.36
• Publications: 2 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 -9 ACMG points.

• BS2: For more information check the summary or visit ClinGen Evidence Repository.
• BA1: For more information check the summary or visit ClinGen Evidence Repository.

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.1455_1460delGGCCAA	p.Ala486_Lys487del	disruptive_inframe_deletion	Exon 12 of 18	NP_001310218.1	O76039-2
	CDKL5	NM_001037343.2		c.1455_1460delGGCCAA	p.Ala486_Lys487del	disruptive_inframe_deletion	Exon 13 of 22	NP_001032420.1	O76039-1
	CDKL5	NM_003159.3		c.1455_1460delGGCCAA	p.Ala486_Lys487del	disruptive_inframe_deletion	Exon 12 of 21	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.1455_1460delGGCCAA	p.Ala486_Lys487del	disruptive_inframe_deletion	Exon 12 of 18	ENSP00000485244.1	O76039-2
	CDKL5	ENST00000379989.6	TSL:1	c.1455_1460delGGCCAA	p.Ala486_Lys487del	disruptive_inframe_deletion	Exon 13 of 22	ENSP00000369325.3	O76039-1
	CDKL5	ENST00000379996.7	TSL:1	c.1455_1460delGGCCAA	p.Ala486_Lys487del	disruptive_inframe_deletion	Exon 12 of 21	ENSP00000369332.3	O76039-1

Frequencies

GnomAD3 genomes AF: 0.0000270 AC: 3 AN: 111061 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.0000328

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: 0.0000378

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000660 AC: 12 AN: 181925 AF XY: 0.0000600

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000329

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000247

Gnomad OTH exome AF: 0.000223

GnomAD4 exome AF: 0.0000985 AC: 108 AN: 1096500 Hom.: 0 AF XY: 0.000113 AC XY: 41 AN XY: 362182

African (AFR) AF: 0.0000380 AC: 1 AN: 26341

American (AMR) AF: 0.000256 AC: 9 AN: 35124

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19325

East Asian (EAS) AF: 0.00 AC: 0 AN: 30173

South Asian (SAS) AF: 0.00 AC: 0 AN: 54063

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40504

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4123

European-Non Finnish (NFE) AF: 0.000114 AC: 96 AN: 840830

Other (OTH) AF: 0.0000435 AC: 2 AN: 46017

GnomAD4 genome AF: 0.0000270 AC: 3 AN: 111061 Hom.: 0 Cov.: 22 AF XY: 0.0000601 AC XY: 2 AN XY: 33303

African (AFR) AF: 0.0000328 AC: 1 AN: 30453

American (AMR) AF: 0.00 AC: 0 AN: 10540

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2643

East Asian (EAS) AF: 0.00 AC: 0 AN: 3525

South Asian (SAS) AF: 0.00 AC: 0 AN: 2606

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5966

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 239

European-Non Finnish (NFE) AF: 0.0000378 AC: 2 AN: 52915

Other (OTH) AF: 0.00 AC: 0 AN: 1500

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000529

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	2	CDKL5 disorder (2)
-	-	1	CDKL5-related disorder (1)
-	-	1	Developmental and epileptic encephalopathy, 2;CN128785:Angelman syndrome-like (1)
-	1	-	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.4
Mutation Taster		=147/53	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs587783114; hg19: chrX-18622494;