rs201652272
Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2
The NM_001142800.2(EYS):c.2234A>G(p.Asn745Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0012 in 1,551,278 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_001142800.2 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Benign. Variant got -8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
EYS | NM_001142800.2 | c.2234A>G | p.Asn745Ser | missense_variant | 14/43 | ENST00000503581.6 | NP_001136272.1 | |
EYS | NM_001292009.2 | c.2234A>G | p.Asn745Ser | missense_variant | 14/44 | NP_001278938.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
EYS | ENST00000503581.6 | c.2234A>G | p.Asn745Ser | missense_variant | 14/43 | 5 | NM_001142800.2 | ENSP00000424243.1 | ||
EYS | ENST00000370621.7 | c.2234A>G | p.Asn745Ser | missense_variant | 14/44 | 1 | ENSP00000359655.3 |
Frequencies
GnomAD3 genomes AF: 0.000670 AC: 102AN: 152172Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000831 AC: 131AN: 157658Hom.: 0 AF XY: 0.000721 AC XY: 60AN XY: 83274
GnomAD4 exome AF: 0.00126 AC: 1767AN: 1398988Hom.: 6 Cov.: 30 AF XY: 0.00119 AC XY: 820AN XY: 690008
GnomAD4 genome AF: 0.000670 AC: 102AN: 152290Hom.: 0 Cov.: 32 AF XY: 0.000671 AC XY: 50AN XY: 74462
ClinVar
Submissions by phenotype
Retinitis pigmentosa 25 Pathogenic:1Uncertain:4
Likely pathogenic, criteria provided, single submitter | research | Ocular Genomics Institute, Massachusetts Eye and Ear | Apr 08, 2021 | The EYS c.2234A>G variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PS1, PM2, PM3. Based on this evidence we have classified this variant as Likely Pathogenic. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Jun 06, 2024 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | Sep 01, 2016 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Jul 20, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Aug 22, 2022 | - - |
not provided Pathogenic:1Uncertain:3Benign:1
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2022 | EYS: BP4 - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Aug 13, 2014 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 25, 2022 | This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 745 of the EYS protein (p.Asn745Ser). This variant is present in population databases (rs201652272, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with autosomal recessive retinitis pigmentosa, and autosomal recessive cone-rod dystrophy (PMID: 21069908, 26103963). 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. ClinVar contains an entry for this variant (Variation ID: 194357). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C45". The serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect 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. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Oct 23, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Nov 21, 2023 | In silico analysis supports that this missense variant does not alter protein structure/function; Observed in at least one homozygous clinically unaffected adult relative of an individual referred for genetic testing at GeneDx; This variant is associated with the following publications: (PMID: 34426522, 20333770, 30755224, 30487145, 21069908, 32037395, 33833316, 31574917, 26659599, 26103963, 28224992, 30937429, 21519034, 32483926) - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 22, 2022 | Variant summary: EYS c.2234A>G (p.Asn745Ser) results in a conservative amino acid change located in the EGF-like calcium-binding domain of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00083 in 157658 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in EYS causing Retinitis Pigmentosa (0.00083 vs 0.0034), allowing no conclusion about variant significance. c.2234A>G has been reported in the literature in individuals affected with Retinitis Pigmentosa. These reports do not provide unequivocal conclusions about association of the variant with Retinitis Pigmentosa. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely pathogenic n=2, VUS n=4). Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Retinal dystrophy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Blueprint Genetics | Jan 31, 2019 | - - |
Retinitis pigmentosa Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Aug 27, 2016 | The EYS c.2234A>G (p.Asn745Ser) variant is a missense variant that has been reported in four studies and identified in a compound heterozygous state with a stop-gained variant in two siblings with autosomal recessive retinitis pigmentosa and in one individual with cone and cone-rod dystrophy as well as in a heterozygous state in two individuals with retinitis pigmentosa in whom a second variant could not be found (Audo et al. 2010; Barragan et al. 2010; Pieras et al. 2011; Boulanger-Scemama et al. 2015). The p.Asn745Ser variant was absent from 728 controls and is reported at a frequency of 0.00134 in the African population of the Exome Aggregation Consortium. Based on the evidence, the p.Asn745Ser variant is classified as a variant of unknown significance but suspicious for pathogenicity for autosomal recessive retinitis pigmentosa. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at