rs41302239
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM1BP4_StrongBS2_Supporting
The NM_206933.4(USH2A):c.5858C>G(p.Ala1953Gly) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000763 in 1,613,850 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_206933.4 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
USH2A | NM_206933.4 | c.5858C>G | p.Ala1953Gly | missense_variant, splice_region_variant | 30/72 | ENST00000307340.8 | NP_996816.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
USH2A | ENST00000307340.8 | c.5858C>G | p.Ala1953Gly | missense_variant, splice_region_variant | 30/72 | 1 | NM_206933.4 | ENSP00000305941 | P1 | |
USH2A | ENST00000674083.1 | c.5858C>G | p.Ala1953Gly | missense_variant, splice_region_variant | 30/73 | ENSP00000501296 |
Frequencies
GnomAD3 genomes AF: 0.000815 AC: 124AN: 152168Hom.: 1 Cov.: 32
GnomAD3 exomes AF: 0.000844 AC: 212AN: 251114Hom.: 0 AF XY: 0.000899 AC XY: 122AN XY: 135714
GnomAD4 exome AF: 0.000758 AC: 1108AN: 1461564Hom.: 3 Cov.: 31 AF XY: 0.000795 AC XY: 578AN XY: 727090
GnomAD4 genome AF: 0.000808 AC: 123AN: 152286Hom.: 1 Cov.: 32 AF XY: 0.000806 AC XY: 60AN XY: 74458
ClinVar
Submissions by phenotype
not provided Uncertain:7Benign:2
Uncertain significance, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Sep 11, 2023 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 24, 2022 | This sequence change replaces alanine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 1953 of the USH2A protein (p.Ala1953Gly). This variant is present in population databases (rs41302239, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with retinitis pigmentosa, retinal dystrophy, and Usher syndrome (PMID: 28041643, 28981474, 29142287). ClinVar contains an entry for this variant (Variation ID: 48546). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Athena Diagnostics | Jul 25, 2019 | - - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2024 | USH2A: BP4 - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jan 03, 2017 | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Dec 03, 2020 | This variant is associated with the following publications: (PMID: 24944099, 27145477, 26868535, 28981474, 28041643, 20507924, 33576794) - |
Usher syndrome type 2A Pathogenic:1Uncertain:3Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital | Feb 11, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jun 10, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Nov 28, 2019 | This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PM1,PP3. - |
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Dec 31, 2019 | - - |
Pathogenic, criteria provided, single submitter | research | Laboratory of Prof. Karen Avraham, Tel Aviv University | Aug 20, 2024 | The p.(Ala1953Gly) is a known recessive variant based on PMID: 20507924. It was detected in an hearing impaired individual with a sloping audiogram, normal-to-profound HL. - |
Retinal dystrophy Uncertain:2
Uncertain significance, no assertion criteria provided | research | NIHR Bioresource Rare Diseases, University of Cambridge | Jan 01, 2015 | - - |
Uncertain significance, criteria provided, single submitter | research | Dept Of Ophthalmology, Nagoya University | Oct 01, 2023 | - - |
not specified Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jun 28, 2019 | The p.Ala1953Gly variant in USH2A has been identified in several individuals with hearing loss, retinitis pigmentosa, and Usher syndrome but has been identified in 0.1% (144/128948) of European chromosomes (http://gnomad.broadinstitute.org). This frequency suggests that the variant may not be pathogenic. Consistent with this, three individuals tested by our laboratory had alternate genetic explanations of their disease, including one individual who was homozygous for the p. Ala1953Gly variant but harbored another homozygous pathogenic USH2A variant. ACMG/AMP criteria applied: BS1_Supporting, BP2, BP5. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 08, 2022 | Variant summary: USH2A c.5858C>G (p.Ala1953Gly) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00084 in 251114 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in USH2A causing Usher Syndrome (0.00084 vs 0.011), allowing no conclusion about variant significance. c.5858C>G has been reported in the literature as a heterozygous genotype in combination with other heterozygous variants in the USH2A gene without phase clearly specified in probands with Retinitis Pigmentosa (RP), Retinal Dystrophies (RD), Pericentral Scotoma, and a reported diagnosis of Usher syndrome (example, Chebil_2016, Comander_2017, Carss_2017, Eandi_2017, Colombo_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Usher Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Thirteen 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 benign, n=3; VUS, n=10). Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Usher syndrome type 2A;C3151138:Retinitis pigmentosa 39 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Retinitis pigmentosa 39 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jul 22, 2021 | - - |
USH2A-related disorder Benign:1
Likely benign, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Sep 03, 2024 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at