rs672601303

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.

• 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: 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_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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDKL5	NM_001323289.2	c.2045_2046delAGinsNNNNNNNNNNNNNNNNNN	p.Glu682delins?????????????????????	missense_variant, splice_region_variant		ENST00000623535.2	NP_001310218.1
CDKL5	NM_001037343.2	c.2045_2046delAGinsNNNNNNNNNNNNNNNNNN	p.Glu682delins?????????????????????	missense_variant, splice_region_variant			NP_001032420.1
CDKL5	NM_003159.3	c.2045_2046delAGinsNNNNNNNNNNNNNNNNNN	p.Glu682delins?????????????????????	missense_variant, splice_region_variant			NP_003150.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDKL5	ENST00000623535.2	c.1999_2000delAGinsNNNNNNNNNNNNNNNNNN	p.Thr667fs	frameshift_variant, missense_variant	Exon 13 of 18	1	NM_001323289.2	ENSP00000485244.1

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 v4.3

Splicing

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

Other links and lift over

hg19: chrX-18627031;