rs672601323

Variant names:

• chrX-18608911-AG-NNNNNNNNNNNNNNNNNN
• ENST00000623535.2:c.1999_2000delAGinsNNNNNNNNNNNNNNNNNN

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PVS1

The ENST00000623535.2(CDKL5):​c.1999_2000delAGinsNNNNNNNNNNNNNNNNNN​(p.Thr667fs) variant causes a frameshift, missense change. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Variant results in nonsense mediated mRNA decay. The gene CDKL5 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 N/A (N/A hom., N/A hem., cov:)
  • Exomes 𝑓: N/A (N/A hom. N/A hem.)
• Consequence: CDKL5 ENST00000623535.2 frameshift, missense
• Clinical Significance: Not reported in ClinVar
• Conservation: No conservation score assigned
• Publications: 0 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: G2P, Orphanet, 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

Specifications for CDKL5 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000623535.2. 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.2045_2046delAGinsNNNNNNNNNNNNNNNNNN	p.Glu682delins?????????????????????	missense splice_region	N/A	NP_001310218.1	O76039-2
	CDKL5	NM_001037343.2		c.2045_2046delAGinsNNNNNNNNNNNNNNNNNN	p.Glu682delins?????????????????????	missense splice_region	N/A	NP_001032420.1	O76039-1
	CDKL5	NM_003159.3		c.2045_2046delAGinsNNNNNNNNNNNNNNNNNN	p.Glu682delins?????????????????????	missense splice_region	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.1999_2000delAGinsNNNNNNNNNNNNNNNNNN	p.Thr667fs	frameshift missense	Exon 13 of 18	ENSP00000485244.1	O76039-2
	CDKL5	ENST00000379989.6	TSL:1	c.1999_2000delAGinsNNNNNNNNNNNNNNNNNN	p.Thr667fs	frameshift missense	Exon 14 of 22	ENSP00000369325.3	O76039-1
	CDKL5	ENST00000379996.7	TSL:1	c.1999_2000delAGinsNNNNNNNNNNNNNNNNNN	p.Thr667fs	frameshift missense	Exon 13 of 21	ENSP00000369332.3	O76039-1

Frequencies

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

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

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chrX-18627031;