6-64081954-A-G
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP5BP4
The NM_001142800.2(EYS):āc.6473T>Cā(p.Leu2158Pro) variant causes a missense change. The variant allele was found at a frequency of 0.0000466 in 1,544,886 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L2158L) has been classified as Likely benign.
Frequency
Consequence
NM_001142800.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
EYS | NM_001142800.2 | c.6473T>C | p.Leu2158Pro | missense_variant | 32/43 | ENST00000503581.6 | |
EYS | NM_001292009.2 | c.6473T>C | p.Leu2158Pro | missense_variant | 32/44 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
EYS | ENST00000503581.6 | c.6473T>C | p.Leu2158Pro | missense_variant | 32/43 | 5 | NM_001142800.2 | A2 | |
EYS | ENST00000370621.7 | c.6473T>C | p.Leu2158Pro | missense_variant | 32/44 | 1 | P2 |
Frequencies
GnomAD3 genomes AF: 0.0000460 AC: 7AN: 152192Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000326 AC: 5AN: 153456Hom.: 0 AF XY: 0.0000368 AC XY: 3AN XY: 81424
GnomAD4 exome AF: 0.0000467 AC: 65AN: 1392694Hom.: 0 Cov.: 28 AF XY: 0.0000349 AC XY: 24AN XY: 687332
GnomAD4 genome AF: 0.0000460 AC: 7AN: 152192Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3AN XY: 74338
ClinVar
Submissions by phenotype
not provided Pathogenic:1Uncertain:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 02, 2024 | This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 2158 of the EYS protein (p.Leu2158Pro). This variant is present in population databases (rs777735735, gnomAD 0.03%). This missense change has been observed in individuals with retinitis pigmentosa (PMID: 28041643, 32581362, 36819107; Invitae). ClinVar contains an entry for this variant (Variation ID: 438204). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on EYS protein function. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | May 17, 2021 | In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 32581362, 28041643) - |
Retinitis pigmentosa 25 Uncertain:2
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 18, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Apr 20, 2022 | - - |
Retinitis pigmentosa Pathogenic:1
Likely pathogenic, no assertion criteria provided | research | NIHR Bioresource Rare Diseases, University of Cambridge | Jan 01, 2015 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at