chr6-65384473-G-GT
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001142800.2(EYS):c.1211dupA(p.Asn404fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000175 in 1,601,590 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.000020 ( 1 hom., cov: 32)
Exomes 𝑓: 0.000017 ( 0 hom. )
Consequence
EYS
NM_001142800.2 frameshift
NM_001142800.2 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 3.05
Genes affected
EYS (HGNC:21555): (eyes shut homolog) The product of this gene contains multiple epidermal growth factor (EGF)-like and LamG domains. The protein is expressed in the photoreceptor layer of the retina, and the gene is mutated in autosomal recessive retinitis pigmentosa. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 6-65384473-G-GT is Pathogenic according to our data. Variant chr6-65384473-G-GT is described in ClinVar as [Likely_pathogenic]. Clinvar id is 636023.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
EYS | NM_001142800.2 | c.1211dupA | p.Asn404fs | frameshift_variant | 8/43 | ENST00000503581.6 | NP_001136272.1 | |
EYS | NM_001292009.2 | c.1211dupA | p.Asn404fs | frameshift_variant | 8/44 | NP_001278938.1 | ||
EYS | NM_001142801.2 | c.1211dupA | p.Asn404fs | frameshift_variant | 8/12 | NP_001136273.1 | ||
EYS | NM_198283.2 | c.1211dupA | p.Asn404fs | frameshift_variant | 7/10 | NP_938024.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
EYS | ENST00000503581.6 | c.1211dupA | p.Asn404fs | frameshift_variant | 8/43 | 5 | NM_001142800.2 | ENSP00000424243.1 | ||
EYS | ENST00000370621.7 | c.1211dupA | p.Asn404fs | frameshift_variant | 8/44 | 1 | ENSP00000359655.3 | |||
EYS | ENST00000393380.6 | c.1211dupA | p.Asn404fs | frameshift_variant | 8/12 | 1 | ENSP00000377042.2 | |||
EYS | ENST00000342421.9 | c.1211dupA | p.Asn404fs | frameshift_variant | 6/9 | 1 | ENSP00000341818.5 |
Frequencies
GnomAD3 genomes AF: 0.0000198 AC: 3AN: 151684Hom.: 1 Cov.: 32
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GnomAD3 exomes AF: 0.0000161 AC: 4AN: 248422Hom.: 0 AF XY: 0.0000223 AC XY: 3AN XY: 134412
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GnomAD4 exome AF: 0.0000172 AC: 25AN: 1449790Hom.: 0 Cov.: 27 AF XY: 0.0000222 AC XY: 16AN XY: 722198
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GnomAD4 genome AF: 0.0000198 AC: 3AN: 151800Hom.: 1 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74194
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Retinitis pigmentosa 25 Pathogenic:3
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Feb 01, 2021 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Sep 17, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 25, 2024 | - - |
Retinitis pigmentosa Pathogenic:2
Likely pathogenic, no assertion criteria provided | research | Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet | Apr 01, 2018 | - - |
Pathogenic, no assertion criteria provided | research | Sharon lab, Hadassah-Hebrew University Medical Center | Jun 23, 2019 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Sep 21, 2023 | This sequence change creates a premature translational stop signal (p.Asn404Lysfs*3) in the EYS gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in EYS are known to be pathogenic (PMID: 18836446, 20333770). This variant is present in population databases (rs764163418, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with retinitis pigmentosa (PMID: 20375346). ClinVar contains an entry for this variant (Variation ID: 636023). For these reasons, this variant has been classified as Pathogenic. - |
Retinal dystrophy Pathogenic:1
Pathogenic, criteria provided, single submitter | research | Dept Of Ophthalmology, Nagoya University | Oct 01, 2023 | - - |
Computational scores
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at