X-18620084-T-A

Variant names:

• chrX-18620084-T-A
• rs3752484
• NM_001323289.2:c.2376+118T>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001323289.2(CDKL5):​c.2376+118T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.404 in 492,998 control chromosomes in the GnomAD database, including 30,439 homozygotes. There are 64,539 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.45 (8739 hom., 14975 hem., cov: 23)
  • Exomes 𝑓: 0.39 (21700 hom. 49564 hem.)
• Consequence: CDKL5 NM_001323289.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4 O:1
• Conservation: PhyloP100: 0.251
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant X-18620084-T-A is Benign according to our data. Variant chrX-18620084-T-A is described in ClinVar as Benign. ClinVar VariationId is 156079.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.656 is higher than 0.05.

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.2376+118T>A		intron	N/A	NP_001310218.1	O76039-2
	CDKL5	NM_001037343.2		c.2376+118T>A		intron	N/A	NP_001032420.1	O76039-1
	CDKL5	NM_003159.3		c.2376+118T>A		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.2376+118T>A		intron	N/A	ENSP00000485244.1	O76039-2
	CDKL5	ENST00000379989.6	TSL:1	c.2376+118T>A		intron	N/A	ENSP00000369325.3	O76039-1
	CDKL5	ENST00000379996.7	TSL:1	c.2376+118T>A		intron	N/A	ENSP00000369332.3	O76039-1

Frequencies

GnomAD3 genomes AF: 0.446 AC: 49610 AN: 111239 Hom.: 8735 Cov.: 23

Gnomad AFR AF: 0.626

Gnomad AMI AF: 0.266

Gnomad AMR AF: 0.631

Gnomad ASJ AF: 0.460

Gnomad EAS AF: 0.679

Gnomad SAS AF: 0.486

Gnomad FIN AF: 0.259

Gnomad MID AF: 0.386

Gnomad NFE AF: 0.311

Gnomad OTH AF: 0.462

GnomAD4 exome AF: 0.391 AC: 149359 AN: 381706 Hom.: 21700 AF XY: 0.407 AC XY: 49564 AN XY: 121764

African (AFR) AF: 0.641 AC: 7048 AN: 10989

American (AMR) AF: 0.736 AC: 14083 AN: 19142

Ashkenazi Jewish (ASJ) AF: 0.448 AC: 5282 AN: 11778

East Asian (EAS) AF: 0.689 AC: 15951 AN: 23137

South Asian (SAS) AF: 0.475 AC: 14250 AN: 29973

European-Finnish (FIN) AF: 0.273 AC: 8648 AN: 31725

Middle Eastern (MID) AF: 0.376 AC: 575 AN: 1529

European-Non Finnish (NFE) AF: 0.322 AC: 74761 AN: 232037

Other (OTH) AF: 0.409 AC: 8761 AN: 21396

GnomAD4 genome AF: 0.446 AC: 49676 AN: 111292 Hom.: 8739 Cov.: 23 AF XY: 0.447 AC XY: 14975 AN XY: 33496

African (AFR) AF: 0.626 AC: 19165 AN: 30603

American (AMR) AF: 0.631 AC: 6597 AN: 10448

Ashkenazi Jewish (ASJ) AF: 0.460 AC: 1209 AN: 2631

East Asian (EAS) AF: 0.679 AC: 2373 AN: 3495

South Asian (SAS) AF: 0.489 AC: 1319 AN: 2696

European-Finnish (FIN) AF: 0.259 AC: 1547 AN: 5981

Middle Eastern (MID) AF: 0.382 AC: 81 AN: 212

European-Non Finnish (NFE) AF: 0.311 AC: 16506 AN: 53030

Other (OTH) AF: 0.460 AC: 698 AN: 1516

Alfa AF: 0.371 Hom.: 2550

Bravo AF: 0.491

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (3)
-	-	1	CDKL5 disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.60
DANN	Benign	0.74
PhyloP100		0.25
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs3752484; hg19: chrX-18638204;