chr8-54628077-TG-T
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_006269.2(RP1):c.4196delG(p.Cys1399LeufsTer5) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,708 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_006269.2 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
RP1 | ENST00000220676.2 | c.4196delG | p.Cys1399LeufsTer5 | frameshift_variant | Exon 4 of 4 | 1 | NM_006269.2 | ENSP00000220676.1 | ||
RP1 | ENST00000637698.1 | c.787+5790delG | intron_variant | Intron 3 of 28 | 5 | ENSP00000490104.1 | ||||
RP1 | ENST00000636932.1 | c.787+5790delG | intron_variant | Intron 3 of 22 | 5 | ENSP00000489857.1 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 exomes AF: 0.00000399 AC: 1AN: 250622Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135662
GnomAD4 exome AF: 0.00000479 AC: 7AN: 1461708Hom.: 0 Cov.: 41 AF XY: 0.00000550 AC XY: 4AN XY: 727146
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Retinitis pigmentosa 1 Pathogenic:1
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not provided Pathogenic:1
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the C-terminus of the RP1 protein. Many variants that disrupt this region have been reported in individuals with either autosomal dominant or autosomal recessive retinitis pigmentosa (PMID: 11527933, 19933189, 29425069, 30027431, 33681214). Therefore, variants that disrupt this region are expected to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 225457). This premature translational stop signal has been observed in individual(s) with clinical features of autosomal recessive retinitis pigmentosa (PMID: 25097241, 29641573, 31253780). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs762951570, gnomAD 0.006%). This sequence change creates a premature translational stop signal (p.Cys1399Leufs*5) in the RP1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 758 amino acid(s) of the RP1 protein. -
Retinal dystrophy Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at