chr11-17612217-G-T
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBP6
The NM_001292063.2(OTOG):c.6179G>T(p.Arg2060Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000818 in 1,549,256 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2060H) has been classified as Uncertain significance.
Frequency
Consequence
NM_001292063.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
OTOG | NM_001292063.2 | c.6179G>T | p.Arg2060Leu | missense_variant | 37/56 | ENST00000399397.6 | |
OTOG | NM_001277269.2 | c.6215G>T | p.Arg2072Leu | missense_variant | 36/55 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
OTOG | ENST00000399397.6 | c.6179G>T | p.Arg2060Leu | missense_variant | 37/56 | 5 | NM_001292063.2 | P2 | |
OTOG | ENST00000399391.7 | c.6215G>T | p.Arg2072Leu | missense_variant | 36/55 | 5 | A2 | ||
OTOG | ENST00000342528.2 | n.3517G>T | non_coding_transcript_exon_variant | 13/22 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.000519 AC: 79AN: 152150Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000581 AC: 86AN: 147896Hom.: 1 AF XY: 0.000652 AC XY: 52AN XY: 79740
GnomAD4 exome AF: 0.000851 AC: 1189AN: 1397106Hom.: 2 Cov.: 31 AF XY: 0.000834 AC XY: 575AN XY: 689150
GnomAD4 genome ? AF: 0.000519 AC: 79AN: 152150Hom.: 0 Cov.: 32 AF XY: 0.000471 AC XY: 35AN XY: 74338
ClinVar
Submissions by phenotype
not provided Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jun 08, 2022 | This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 2072 of the OTOG protein (p.Arg2072Leu). This variant is present in population databases (rs188527711, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with OTOG-related conditions. ClinVar contains an entry for this variant (Variation ID: 229097). 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: "Tolerated"; PolyPhen-2: "Probably 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. - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | May 13, 2021 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Dec 07, 2017 | Variant classified as Uncertain Significance - Favor Benign. The p.Arg2072Leu va riant in OTOG has now been identified by our laboratory in 2 Caucasian individua l with hearing loss; however, one of these individuals carried variants in a dif ferent gene that were sufficient to explain their hearing loss. This variant has also been identified in 0.1% (73/66920) of European chromosomes, including 1 ho mozygous individual, by the Genome Aggregation Database (gnomAD, http://gnomad.b roadinstitute.org; rs188527711). Although this variant has been seen in the gene ral population, its frequency is not high enough to rule out a pathogenic role. Computational prediction tools and conservation analysis do not provide strong s upport for or against an impact to the protein. In summary, while the clinical s ignificance of the p.Arg2072Leu variant is uncertain, these data suggest that it is more likely to be benign. ACMG/AMP criteria applied: BP5. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at