X-18579749-C-A

Variant names:

• chrX-18579749-C-A
• rs4825261
• NM_001323289.2:c.283-99C>A

Variant summary

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

The NM_003159.3(CDKL5):​c.283-99C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.314 in 781,995 control chromosomes in the GnomAD database, including 28,867 homozygotes. There are 71,175 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.28 (3433 hom., 9251 hem., cov: 23)
  • Exomes 𝑓: 0.32 (25434 hom. 61924 hem.)
• Consequence: CDKL5 NM_003159.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4 O:1
• Conservation: PhyloP100: -0.739
• 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=-0.82).
• BP6: Variant X-18579749-C-A is Benign according to our data. Variant chrX-18579749-C-A is described in ClinVar as Benign. ClinVar VariationId is 156085.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.439 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003159.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDKL5	NM_001323289.2	MANE Select	c.283-99C>A		intron	N/A	NP_001310218.1
	CDKL5	NM_001037343.2		c.283-99C>A		intron	N/A	NP_001032420.1
	CDKL5	NM_003159.3		c.283-99C>A		intron	N/A	NP_003150.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDKL5	ENST00000623535.2	TSL:1 MANE Select	c.283-99C>A		intron	N/A	ENSP00000485244.1
	CDKL5	ENST00000379989.6	TSL:1	c.283-99C>A		intron	N/A	ENSP00000369325.3
	CDKL5	ENST00000379996.7	TSL:1	c.283-99C>A		intron	N/A	ENSP00000369332.3

Frequencies

GnomAD3 genomes AF: 0.283 AC: 31182 AN: 110051 Hom.: 3437 Cov.: 23

Gnomad AFR AF: 0.165

Gnomad AMI AF: 0.266

Gnomad AMR AF: 0.425

Gnomad ASJ AF: 0.410

Gnomad EAS AF: 0.459

Gnomad SAS AF: 0.411

Gnomad FIN AF: 0.260

Gnomad MID AF: 0.285

Gnomad NFE AF: 0.302

Gnomad OTH AF: 0.283

GnomAD4 exome AF: 0.319 AC: 214153 AN: 671895 Hom.: 25434 AF XY: 0.337 AC XY: 61924 AN XY: 183723

African (AFR) AF: 0.152 AC: 2601 AN: 17061

American (AMR) AF: 0.523 AC: 14547 AN: 27820

Ashkenazi Jewish (ASJ) AF: 0.392 AC: 6007 AN: 15323

East Asian (EAS) AF: 0.465 AC: 12650 AN: 27215

South Asian (SAS) AF: 0.413 AC: 16360 AN: 39630

European-Finnish (FIN) AF: 0.270 AC: 10155 AN: 37625

Middle Eastern (MID) AF: 0.326 AC: 916 AN: 2813

European-Non Finnish (NFE) AF: 0.298 AC: 141111 AN: 473233

Other (OTH) AF: 0.315 AC: 9806 AN: 31175

GnomAD4 genome AF: 0.283 AC: 31182 AN: 110100 Hom.: 3433 Cov.: 23 AF XY: 0.285 AC XY: 9251 AN XY: 32450

African (AFR) AF: 0.165 AC: 5024 AN: 30471

American (AMR) AF: 0.426 AC: 4391 AN: 10316

Ashkenazi Jewish (ASJ) AF: 0.410 AC: 1078 AN: 2627

East Asian (EAS) AF: 0.458 AC: 1590 AN: 3470

South Asian (SAS) AF: 0.414 AC: 1084 AN: 2621

European-Finnish (FIN) AF: 0.260 AC: 1469 AN: 5651

Middle Eastern (MID) AF: 0.273 AC: 57 AN: 209

European-Non Finnish (NFE) AF: 0.302 AC: 15887 AN: 52566

Other (OTH) AF: 0.283 AC: 423 AN: 1497

Alfa AF: 0.168 Hom.: 897

Bravo AF: 0.298

ClinVar

ClinVar submissions as Germline

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	-0.82
CADD	Benign	0.074
DANN	Benign	0.56
PhyloP100		-0.74
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: rs4825261; hg19: chrX-18597869; COSMIC: COSV66110067; COSMIC: COSV66110067;