chr1-215675568-G-A
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PM2
The NM_206933.4(USH2A):c.12343C>T(p.Arg4115Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000527 in 1,614,040 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R4115H) has been classified as Likely benign.
Frequency
Consequence
NM_206933.4 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
USH2A | NM_206933.4 | c.12343C>T | p.Arg4115Cys | missense_variant | 63/72 | ENST00000307340.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
USH2A | ENST00000307340.8 | c.12343C>T | p.Arg4115Cys | missense_variant | 63/72 | 1 | NM_206933.4 | P1 | |
USH2A | ENST00000674083.1 | c.12343C>T | p.Arg4115Cys | missense_variant | 63/73 |
Frequencies
GnomAD3 genomes ? AF: 0.000532 AC: 81AN: 152114Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000307 AC: 77AN: 250496Hom.: 0 AF XY: 0.000332 AC XY: 45AN XY: 135388
GnomAD4 exome AF: 0.000527 AC: 770AN: 1461808Hom.: 0 Cov.: 37 AF XY: 0.000517 AC XY: 376AN XY: 727192
GnomAD4 genome ? AF: 0.000532 AC: 81AN: 152232Hom.: 0 Cov.: 32 AF XY: 0.000538 AC XY: 40AN XY: 74416
ClinVar
Submissions by phenotype
not provided Uncertain:3Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jun 29, 2022 | Identified in patients with Usher syndrome or retinitis pigmentosa in published literature, although additional clinical information and familial segregation information were not provided in some cases (Garcia-Garcia et al., 2011; Pierrache et al., 2016; van Huet et al., 2015); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30245029, 25999674, 15015129, 26927203, 22334370, 18273898, 16963483, 27460420, 22004887, 17405132, 32483926) - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | May 23, 2017 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Oct 14, 2021 | - - |
not specified Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Apr 24, 2015 | p.Arg4115Cys in exon 63 of USH2A: This variant has been reported in 8 individual s with Usher syndrome and 2 individuals with retinitis pigmentosa. However, 3 of the individuals with Usher syndrome carried another pathogenic variant on the s ame allele and 4 of the 10 individuals carried 2 pathogenic variants in USH2A th at were sufficient to explain their disease. As a result, this variant is not ex pected to have clinical significance. It has also been identified in 32/66436 Eu ropean chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadi nstitute.org; dbSNP rs111033275). - |
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 23, 2023 | Variant summary: USH2A c.12343C>T (p.Arg4115Cys) results in a non-conservative amino acid change located in the Fibronectin type III (IPR003961) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00031 in 250496 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in USH2A causing Usher Syndrome (0.00031 vs 0.011), allowing no conclusion about variant significance. c.12343C>T has been reported in the literature in individuals affected with Usher Syndrome and Retinitis Pigmentosa (e.g. Pierrache_2016, Garcia-Garcia_2011, Reurink_2023, vanHuet_2015, Azaiez_2018) without evidence for causality. Additionally, co-occurrences with other pathogenic variants have been reported in cis with this variant (USH2A c.13274C>T, p.T4425M; USH2A c.13274C>T, p.T4425M; USH2A c.1876C>T, p.R626Ter) (e.g. vanWijk_2004, Bonnet_2016, Dreyer_2008) , providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 30245029, 27460420, 18273898, 22004887, 26927203, 25999674, 15015129, 30902645). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified as benign/likely benign (n=3) and VUS (n=4). Based on the evidence outlined above, the variant was classified as likely benign. - |
Retinal dystrophy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Blueprint Genetics | Apr 16, 2019 | - - |
Usher syndrome type 2A Benign:1
Benign, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at