1-215625810-G-A
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_206933.4(USH2A):c.15580C>T(p.Arg5194Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000018 in 1,613,904 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 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. R5194H) has been classified as Likely benign.
Frequency
Consequence
NM_206933.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
USH2A | ENST00000307340.8 | c.15580C>T | p.Arg5194Cys | missense_variant | Exon 72 of 72 | 1 | NM_206933.4 | ENSP00000305941.3 | ||
USH2A | ENST00000674083.1 | c.15652C>T | p.Arg5218Cys | missense_variant | Exon 73 of 73 | ENSP00000501296.1 |
Frequencies
GnomAD3 genomes AF: 0.0000329 AC: 5AN: 152100Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000437 AC: 11AN: 251440Hom.: 0 AF XY: 0.0000736 AC XY: 10AN XY: 135878
GnomAD4 exome AF: 0.0000164 AC: 24AN: 1461804Hom.: 0 Cov.: 31 AF XY: 0.0000248 AC XY: 18AN XY: 727208
GnomAD4 genome AF: 0.0000329 AC: 5AN: 152100Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3AN XY: 74310
ClinVar
Submissions by phenotype
not provided Uncertain:2
In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 5194 of the USH2A protein (p.Arg5194Cys). This variant is present in population databases (rs751811618, gnomAD 0.02%). 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: 1217401). 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 with a negative predictive value of 95%. 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. -
Usher syndrome type 2A Uncertain:2
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Retinitis pigmentosa 39 Uncertain:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at