NM_001323289.2:c.283-99C>T

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_001323289.2(CDKL5):​c.283-99C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000128 in 783,246 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 29 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00023 (0 hom., 9 hem., cov: 23)
  • Exomes 𝑓: 0.00011 (0 hom. 20 hem.)
• Consequence: CDKL5 NM_001323289.2 intron
• Clinical Significance: Not reported in ClinVar
• 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000227 (25/110156) while in subpopulation AMR AF = 0.00165 (17/10321). AF 95% confidence interval is 0.00105. There are 0 homozygotes in GnomAd4. There are 9 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High AC in GnomAd4 at 25 XL,AD gene.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDKL5	NM_001323289.2	MANE Select	c.283-99C>T		intron	N/A	NP_001310218.1
	CDKL5	NM_001037343.2		c.283-99C>T		intron	N/A	NP_001032420.1
	CDKL5	NM_003159.3		c.283-99C>T		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>T		intron	N/A	ENSP00000485244.1
	CDKL5	ENST00000379989.6	TSL:1	c.283-99C>T		intron	N/A	ENSP00000369325.3
	CDKL5	ENST00000379996.7	TSL:1	c.283-99C>T		intron	N/A	ENSP00000369332.3

Frequencies

GnomAD3 genomes AF: 0.000227 AC: 25 AN: 110105 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00165

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: 0.000152

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000111 AC: 75 AN: 673090 Hom.: 0 AF XY: 0.000109 AC XY: 20 AN XY: 183842

African (AFR) AF: 0.00 AC: 0 AN: 17079

American (AMR) AF: 0.000539 AC: 15 AN: 27849

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15332

East Asian (EAS) AF: 0.00 AC: 0 AN: 27236

South Asian (SAS) AF: 0.0000252 AC: 1 AN: 39663

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37653

Middle Eastern (MID) AF: 0.00106 AC: 3 AN: 2819

European-Non Finnish (NFE) AF: 0.000105 AC: 50 AN: 474246

Other (OTH) AF: 0.000192 AC: 6 AN: 31213

GnomAD4 genome AF: 0.000227 AC: 25 AN: 110156 Hom.: 0 Cov.: 23 AF XY: 0.000277 AC XY: 9 AN XY: 32480

African (AFR) AF: 0.00 AC: 0 AN: 30485

American (AMR) AF: 0.00165 AC: 17 AN: 10321

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2627

East Asian (EAS) AF: 0.00 AC: 0 AN: 3473

South Asian (SAS) AF: 0.00 AC: 0 AN: 2621

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5658

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 209

European-Non Finnish (NFE) AF: 0.000152 AC: 8 AN: 52592

Other (OTH) AF: 0.00 AC: 0 AN: 1497

Alfa AF: 0.00 Hom.: 897

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.088
DANN	Benign	0.65
PhyloP100		-0.74
Mutation Taster		=100/0	polymorphism

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;