chrX-18642015-T-TG
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Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_StrongPM2
The NM_000330.4(RS1):c.663_664insC(p.Lys222GlnfsTer42) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000911 in 1,097,694 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. Variant has been reported in ClinVar as Uncertain significance (no stars).
Frequency
Genomes: not found (cov: 23)
Exomes 𝑓: 9.1e-7 ( 0 hom. 0 hem. )
Consequence
RS1
NM_000330.4 frameshift
NM_000330.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 1.21
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 4 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RS1 | NM_000330.4 | c.663_664insC | p.Lys222GlnfsTer42 | frameshift_variant | 6/6 | ENST00000379984.4 | |
RS1 | XM_047442337.1 | c.567_568insC | p.Lys190GlnfsTer42 | frameshift_variant | 4/4 | ||
CDKL5 | NM_001037343.2 | c.2714-3991dup | intron_variant | ||||
CDKL5 | NM_003159.3 | c.2714-3991dup | intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RS1 | ENST00000379984.4 | c.663_664insC | p.Lys222GlnfsTer42 | frameshift_variant | 6/6 | 1 | NM_000330.4 | P1 | |
CDKL5 | ENST00000379989.6 | c.2714-3991dup | intron_variant | 1 | |||||
CDKL5 | ENST00000379996.7 | c.2714-3991dup | intron_variant | 1 | |||||
RS1 | ENST00000476595.1 | n.1154_1155insC | non_coding_transcript_exon_variant | 5/5 | 1 |
Frequencies
GnomAD3 genomes Cov.: 23
GnomAD3 genomes
Cov.:
23
GnomAD4 exome AF: 9.11e-7 AC: 1AN: 1097694Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 363246
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GnomAD4 genome Cov.: 23
GnomAD4 genome
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23
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: no assertion criteria provided
LINK: link
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, no assertion criteria provided | literature only | SN ONGC Dept of Genetics and Molecular biology Vision Research Foundation | - | - - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at