rs146445078
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6
The NM_206933.4(USH2A):āc.9203T>Cā(p.Val3068Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000569 in 1,613,828 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict 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. V3068M) 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_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
USH2A | NM_206933.4 | c.9203T>C | p.Val3068Ala | missense_variant | 46/72 | ENST00000307340.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
USH2A | ENST00000307340.8 | c.9203T>C | p.Val3068Ala | missense_variant | 46/72 | 1 | NM_206933.4 | P1 | |
USH2A | ENST00000674083.1 | c.9203T>C | p.Val3068Ala | missense_variant | 46/73 |
Frequencies
GnomAD3 genomes ? AF: 0.000473 AC: 72AN: 152208Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000411 AC: 103AN: 250692Hom.: 0 AF XY: 0.000391 AC XY: 53AN XY: 135468
GnomAD4 exome AF: 0.000579 AC: 846AN: 1461502Hom.: 0 Cov.: 31 AF XY: 0.000568 AC XY: 413AN XY: 727040
GnomAD4 genome ? AF: 0.000473 AC: 72AN: 152326Hom.: 0 Cov.: 33 AF XY: 0.000416 AC XY: 31AN XY: 74490
ClinVar
Submissions by phenotype
not provided Uncertain:2Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Mar 06, 2023 | Reported in an individual with hearing loss who also harbored a nonsense variant on the same USH2A allele (in cis), however, this individual did not have an additional disease-causing variant on the opposite allele (in trans) (Tang et al., 2015); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25991456, 32707200, 32483926) - |
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2016 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
Usher syndrome type 2A Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Oct 01, 2021 | NM_206933.2(USH2A):c.9203T>C(V3068A) is a missense variant classified as a variant of uncertain significance in the context of USH2A-related disorders. V3068A has been observed in cases with relevant disease (PMID: 25991456). Functional assessments of this variant are not available in the literature. V3068A has been observed in population frequency databases (gnomAD: NFE 0.07%). In summary, there is insufficient evidence to classify NM_206933.2(USH2A):c.9203T>C(V3068A) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening. - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Aug 15, 2017 | p.Val3068Ala in exon 46 of USH2A: This variant is not expected to have clinical significance because of a lack of conservation across species including mammals. Of note, rat, mouse and opossum have an alanine at this position despite high n earby amino acid conservation. It has been identified in 85/126144 of European c hromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstit ute.org; dbSNP rs146445078). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at