rs1555957573

Positions:

• chrX-18646096-GTC-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP6_Moderate

The NM_003159.3(CDKL5):​c.2797+8_2797+9delCT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000455 in 1,098,106 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0000046 (0 hom. 1 hem.)
• Consequence: CDKL5 NM_003159.3 splice_region, intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.164

Genes affected

RS1 (HGNC:10457): (retinoschisin 1) This gene encodes an extracellular protein that plays a crucial role in the cellular organization of the retina. The encoded protein is assembled and secreted from photoreceptors and bipolar cells as a homo-oligomeric protein complex. Mutations in this gene are responsible for X-linked retinoschisis, a common, early-onset macular degeneration in males that results in a splitting of the inner layers of the retina and severe loss in vision. [provided by RefSeq, Oct 2008]

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant X-18646096-GTC-G is Benign according to our data. Variant chrX-18646096-GTC-G is described in ClinVar as [Likely_benign]. Clinvar id is 533393.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RS1	NM_000330.4	c.326+1093_326+1094delGA		intron_variant		ENST00000379984.4	NP_000321.1
CDKL5	NM_001037343.2	c.2797+8_2797+9delCT		splice_region_variant, intron_variant			NP_001032420.1
CDKL5	NM_003159.3	c.2797+8_2797+9delCT		splice_region_variant, intron_variant			NP_003150.1
RS1	XM_047442337.1	c.230+1093_230+1094delGA		intron_variant			XP_047298293.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RS1	ENST00000379984.4	c.326+1093_326+1094delGA		intron_variant		1	NM_000330.4	ENSP00000369320.3
CDKL5	ENST00000379989.6	c.2797+7_2797+8delTC		splice_region_variant, intron_variant		1		ENSP00000369325.3
CDKL5	ENST00000379996.7	c.2797+7_2797+8delTC		splice_region_variant, intron_variant		1		ENSP00000369332.3
RS1	ENST00000476595.1	n.817+1093_817+1094delGA		intron_variant		1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 0.00000455 AC: 5 AN: 1098106 Hom.: 0 AF XY: 0.00000275 AC XY: 1 AN XY: 363462

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000331

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000868

GnomAD4 genome Cov.: 22

Bravo AF: 0.0000151

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Developmental and epileptic encephalopathy, 2;CN128785:Angelman syndrome-like Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 19, 2023

- -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs1555957573; hg19: chrX-18664216;