rs762212630
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM1PM2BP4_Strong
The NM_001142800.2(EYS):āc.2892A>Cā(p.Glu964Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000155 in 1,546,740 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E964K) has been classified as Uncertain significance.
Frequency
Consequence
NM_001142800.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
EYS | NM_001142800.2 | c.2892A>C | p.Glu964Asp | missense_variant | 19/43 | ENST00000503581.6 | |
EYS | NM_001292009.2 | c.2892A>C | p.Glu964Asp | missense_variant | 19/44 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
EYS | ENST00000503581.6 | c.2892A>C | p.Glu964Asp | missense_variant | 19/43 | 5 | NM_001142800.2 | A2 | |
EYS | ENST00000370621.7 | c.2892A>C | p.Glu964Asp | missense_variant | 19/44 | 1 | P2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000198 AC: 3AN: 151850Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000519 AC: 8AN: 154094Hom.: 0 AF XY: 0.0000735 AC XY: 6AN XY: 81642
GnomAD4 exome AF: 0.0000151 AC: 21AN: 1394772Hom.: 0 Cov.: 29 AF XY: 0.0000160 AC XY: 11AN XY: 687910
GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 151968Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3AN XY: 74256
ClinVar
Submissions by phenotype
Retinal dystrophy Pathogenic:1
Pathogenic, criteria provided, single submitter | research | Dept Of Ophthalmology, Nagoya University | Oct 01, 2023 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 15, 2023 | Variant summary: EYS c.2892A>C (p.Glu964Asp) results in a conservative amino acid change in the encoded protein sequence. Four of four in-silico tools predict a benign effect of the variant on protein function. c.2892A>C has been reported in the literature as co-occurring with EYS c.2886C>G (p.Phe962Leu) in all instances ascertained among individuals affected with features of Leber congenital amaurosis (LCA) (example, Eisenberger_2013) or Retinitis Pigmentosa (example, Koyanagi_2019, Numa_2020, Gao_2022). In at-least two of these ascertainments, this variant combination also occurred along with a third EYS allele, again without phase specifications, among individuals affected with Retinitis Pigmentosa (n=2, c.8868delT (p.Ala2957fs), Koyanagi_2019 and n=1, c.2582G>A (p.Gly843Asp), Numa_2020). Furthermore, this variant combination also occurred without phase specifications, and therefore as a non-informative genotype alongside a majority concordant benign/likely benign EYS variant c.5510G>C (p.Trp1837Ser) in an individual with LCA (Eisenberger_2013). These report(s) do not provide unequivocal conclusions about association of the variant with Retinitis Pigmentosa or Leber congenital amaurosis. Both these variant alleles are found at a frequency of 5.2e-05 in 154094 and 153916 control chromosomes respectively in the gnomAD (v2) database, further supporting a co-occuring haplotype. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 24265693, 34689181, 31213501, 33247286). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant in isolation was classified as uncertain significance. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 17, 2022 | This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 964 of the EYS protein (p.Glu964Asp). This variant is present in population databases (rs762212630, gnomAD 0.06%). This missense change has been observed in individual(s) with EYS-related conditions (PMID: 24265693, 33247286). ClinVar contains an entry for this variant (Variation ID: 554346). 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 available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Retinitis pigmentosa 25 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Oct 16, 2017 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at