NM_153676.4:c.2240A>G
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_153676.4(USH1C):āc.2240A>Gā(p.Gln747Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000013 in 1,612,836 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 (ā ā ).
Frequency
Consequence
NM_153676.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
USH1C | NM_153676.4 | c.2240A>G | p.Gln747Arg | missense_variant | Exon 22 of 27 | ENST00000005226.12 | NP_710142.1 | |
USH1C | NM_005709.4 | c.1340A>G | p.Gln447Arg | missense_variant | Exon 17 of 21 | ENST00000318024.9 | NP_005700.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
USH1C | ENST00000005226.12 | c.2240A>G | p.Gln747Arg | missense_variant | Exon 22 of 27 | 5 | NM_153676.4 | ENSP00000005226.7 | ||
USH1C | ENST00000318024.9 | c.1340A>G | p.Gln447Arg | missense_variant | Exon 17 of 21 | 1 | NM_005709.4 | ENSP00000317018.4 |
Frequencies
GnomAD3 genomes AF: 0.0000789 AC: 12AN: 152164Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000402 AC: 1AN: 248536Hom.: 0 AF XY: 0.00000744 AC XY: 1AN XY: 134364
GnomAD4 exome AF: 0.00000616 AC: 9AN: 1460554Hom.: 0 Cov.: 33 AF XY: 0.00000551 AC XY: 4AN XY: 726406
GnomAD4 genome AF: 0.0000788 AC: 12AN: 152282Hom.: 0 Cov.: 33 AF XY: 0.000107 AC XY: 8AN XY: 74462
ClinVar
Submissions by phenotype
not provided Uncertain:2
This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 447 of the USH1C protein (p.Gln447Arg). This variant is present in population databases (rs201600193, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with USH1C-related conditions. ClinVar contains an entry for this variant (Variation ID: 178564). 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. -
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 -
not specified Uncertain:1
The Gln747Arg variant in USH1C has not been identified in individuals with heari ng loss, but has been identified in 0.02% (1/4400) of African American chromosom es from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs. washington.edu/EVS/; dbSNP rs201600193). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogeni c role. Computational analyses (biochemical amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) do not provide strong support for or against an impact to the protein. It should be noted that this variant occurs in exon 20 o f USH1C that is expressed in the ear and not the eye and therefore would likely only be relevant to nonsyndromic hearing loss, not Usher syndrome. In summary, a dditional data is needed to determine the clinical significance of this variant. -
Usher syndrome type 1C;C1865870:Autosomal recessive nonsyndromic hearing loss 18A Uncertain:1
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Usher syndrome type 1C Uncertain:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at