X-18579749-C-G

Variant names:

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

Variant summary

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

The NM_003159.3(CDKL5):​c.283-99C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000327 in 673,090 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 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: not found (cov: 23)
  • Exomes 𝑓: 0.000033 (0 hom. 3 hem.)
• Consequence: CDKL5 NM_003159.3 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=-0.87).
• BS1: Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.0000327 (22/673090) while in subpopulation NFE AF = 0.0000464 (22/474246). AF 95% confidence interval is 0.0000313. There are 0 homozygotes in GnomAdExome4. There are 3 alleles in the male GnomAdExome4 subpopulation. This position passed quality control check.
• BS2: High AC in GnomAdExome4 at 22 XL,AD gene.

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>G		intron	N/A	NP_001310218.1
	CDKL5	NM_001037343.2		c.283-99C>G		intron	N/A	NP_001032420.1
	CDKL5	NM_003159.3		c.283-99C>G		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>G		intron	N/A	ENSP00000485244.1
	CDKL5	ENST00000379989.6	TSL:1	c.283-99C>G		intron	N/A	ENSP00000369325.3
	CDKL5	ENST00000379996.7	TSL:1	c.283-99C>G		intron	N/A	ENSP00000369332.3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.0000327 AC: 22 AN: 673090 Hom.: 0 AF XY: 0.0000163 AC XY: 3 AN XY: 183842

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

American (AMR) AF: 0.00 AC: 0 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: 0.00 AC: 0 AN: 39663

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2819

European-Non Finnish (NFE) AF: 0.0000464 AC: 22 AN: 474246

Other (OTH) AF: 0.00 AC: 0 AN: 31213

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 897

Bravo AF: 0.0000151

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.076
DANN	Benign	0.59
PhyloP100		-0.74

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;