X-18642024-A-G
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000330.4(RS1):c.655T>C(p.Cys219Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C219G) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000330.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
RS1 | NM_000330.4 | c.655T>C | p.Cys219Arg | missense_variant | Exon 6 of 6 | ENST00000379984.4 | NP_000321.1 | |
RS1 | XM_047442337.1 | c.559T>C | p.Cys187Arg | missense_variant | Exon 4 of 4 | XP_047298293.1 | ||
CDKL5 | NM_001037343.2 | c.2714-3983A>G | intron_variant | Intron 19 of 21 | NP_001032420.1 | |||
CDKL5 | NM_003159.3 | c.2714-3983A>G | intron_variant | Intron 18 of 20 | NP_003150.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
RS1 | ENST00000379984.4 | c.655T>C | p.Cys219Arg | missense_variant | Exon 6 of 6 | 1 | NM_000330.4 | ENSP00000369320.3 | ||
CDKL5 | ENST00000379989.6 | c.2714-3983A>G | intron_variant | Intron 19 of 21 | 1 | ENSP00000369325.3 | ||||
CDKL5 | ENST00000379996.7 | c.2714-3983A>G | intron_variant | Intron 18 of 20 | 1 | ENSP00000369332.3 | ||||
RS1 | ENST00000476595.1 | n.1146T>C | non_coding_transcript_exon_variant | Exon 5 of 5 | 1 |
Frequencies
GnomAD3 genomes Cov.: 23
GnomAD4 exome Cov.: 31
GnomAD4 genome Cov.: 23
ClinVar
Submissions by phenotype
Retinal dystrophy Pathogenic:2
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not provided Pathogenic:1Other:1
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This variant disrupts the p.Cys219 amino acid residue in RS1. Other variant(s) that disrupt this residue have been observed in individuals with RS1-related conditions (PMID: 9618178, 20061330, 30652005), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been observed in individual(s) with retinoschisis (PMID: 9618178). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 99015). This variant is not present in population databases (ExAC no frequency). This sequence change replaces cysteine with arginine at codon 219 of the RS1 protein (p.Cys219Arg). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and arginine. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at