1-215675549-C-T
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PM5
The NM_206933.4(USH2A):c.12362G>A(p.Arg4121His) variant causes a missense change. The variant allele was found at a frequency of 0.0000112 in 1,613,964 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R4121C) has been classified as Uncertain significance.
Frequency
Consequence
NM_206933.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
USH2A | NM_206933.4 | c.12362G>A | p.Arg4121His | missense_variant | 63/72 | ENST00000307340.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
USH2A | ENST00000307340.8 | c.12362G>A | p.Arg4121His | missense_variant | 63/72 | 1 | NM_206933.4 | P1 | |
USH2A | ENST00000674083.1 | c.12362G>A | p.Arg4121His | missense_variant | 63/73 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152022Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000280 AC: 7AN: 250436Hom.: 0 AF XY: 0.00000739 AC XY: 1AN XY: 135362
GnomAD4 exome AF: 0.0000103 AC: 15AN: 1461824Hom.: 0 Cov.: 37 AF XY: 0.00000550 AC XY: 4AN XY: 727210
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152140Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74378
ClinVar
Submissions by phenotype
Usher syndrome type 2A Uncertain:2
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Jan 24, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Nov 04, 2023 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Apr 10, 2012 | The Arg4121His variant in USH2A has not been reported in the literature nor prev iously identified by our laboratory. Computational analyses (biochemical amino a cid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) do not provide str ong support for or against an impact to the protein. In summary, the clinical si gnificance of this variant cannot be determined with certainty. - |
Usher syndrome type 2A;C3151138:Retinitis pigmentosa 39 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Jun 30, 2017 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 17, 2022 | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 4121 of the USH2A protein (p.Arg4121His). This variant is present in population databases (rs397517980, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with USH2A-related conditions. ClinVar contains an entry for this variant (Variation ID: 48398). 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) performed at Invitae indicates that this missense variant is not expected to disrupt USH2A 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 39 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Nov 04, 2023 | - - |
Retinal dystrophy Uncertain:1
Uncertain significance, criteria provided, single submitter | research | Dept Of Ophthalmology, Nagoya University | Oct 01, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at