chrX-18524039-C-T

Variant names:

• chrX-18524039-C-T
• rs5909187
• NM_001323289.2:c.99+13185C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001323289.2(CDKL5):​c.99+13185C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. 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 0.82 (26587 hom., 26629 hem., cov: 22)
  • Failed GnomAD Quality Control
• Consequence: CDKL5 NM_001323289.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.507
• Publications: 3 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).

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.99+13185C>T		intron	N/A	NP_001310218.1	O76039-2
	CDKL5	NM_001037343.2		c.99+13185C>T		intron	N/A	NP_001032420.1	O76039-1
	CDKL5	NM_003159.3		c.99+13185C>T		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.99+13185C>T		intron	N/A	ENSP00000485244.1	O76039-2
	CDKL5	ENST00000379989.6	TSL:1	c.99+13185C>T		intron	N/A	ENSP00000369325.3	O76039-1
	CDKL5	ENST00000379996.7	TSL:1	c.99+13185C>T		intron	N/A	ENSP00000369332.3	O76039-1

Frequencies

GnomAD3 genomes AF: 0.821 AC: 90579 AN: 110342 Hom.: 26586 Cov.: 22

Gnomad AFR AF: 0.925

Gnomad AMI AF: 0.646

Gnomad AMR AF: 0.875

Gnomad ASJ AF: 0.816

Gnomad EAS AF: 0.862

Gnomad SAS AF: 0.820

Gnomad FIN AF: 0.708

Gnomad MID AF: 0.759

Gnomad NFE AF: 0.762

Gnomad OTH AF: 0.832

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.821 AC: 90634 AN: 110394 Hom.: 26587 Cov.: 22 AF XY: 0.817 AC XY: 26629 AN XY: 32580

African (AFR) AF: 0.925 AC: 28130 AN: 30407

American (AMR) AF: 0.876 AC: 9046 AN: 10331

Ashkenazi Jewish (ASJ) AF: 0.816 AC: 2150 AN: 2634

East Asian (EAS) AF: 0.861 AC: 3018 AN: 3504

South Asian (SAS) AF: 0.820 AC: 2161 AN: 2636

European-Finnish (FIN) AF: 0.708 AC: 4059 AN: 5734

Middle Eastern (MID) AF: 0.767 AC: 165 AN: 215

European-Non Finnish (NFE) AF: 0.762 AC: 40219 AN: 52760

Other (OTH) AF: 0.834 AC: 1254 AN: 1504

Alfa AF: 0.778 Hom.: 67775

Bravo AF: 0.838

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	1.7
DANN	Benign	0.72
PhyloP100		-0.51
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: rs5909187; hg19: chrX-18542159;