rs727504893
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_206933.4(USH2A):c.632G>A(p.Trp211*) variant causes a stop gained change. The variant allele was found at a frequency of 0.000000685 in 1,460,908 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Consequence
USH2A
NM_206933.4 stop_gained
NM_206933.4 stop_gained
Scores
4
2
1
Clinical Significance
Conservation
PhyloP100: 5.82
Genes affected
USH2A (HGNC:12601): (usherin) This gene encodes a protein that contains laminin EGF motifs, a pentaxin domain, and many fibronectin type III motifs. The protein is found in the basement membrane, and may be important in development and homeostasis of the inner ear and retina. Mutations within this gene have been associated with Usher syndrome type IIa and retinitis pigmentosa. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 1-216418533-C-T is Pathogenic according to our data. Variant chr1-216418533-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 179482.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
USH2A | NM_206933.4 | c.632G>A | p.Trp211* | stop_gained | 3/72 | ENST00000307340.8 | NP_996816.3 | |
USH2A | NM_007123.6 | c.632G>A | p.Trp211* | stop_gained | 3/21 | NP_009054.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
USH2A | ENST00000307340.8 | c.632G>A | p.Trp211* | stop_gained | 3/72 | 1 | NM_206933.4 | ENSP00000305941.3 | ||
USH2A | ENST00000366942.3 | c.632G>A | p.Trp211* | stop_gained | 3/21 | 1 | ENSP00000355909.3 | |||
USH2A | ENST00000674083.1 | c.632G>A | p.Trp211* | stop_gained | 3/73 | ENSP00000501296.1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome AF: 6.85e-7 AC: 1AN: 1460908Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0AN XY: 726758
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GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Usher syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 17, 2023 | Variant summary: USH2A c.632G>A (p.Trp211X) results in a premature termination codon and is predicted to cause absence of the protein due to nonsense mediated decay, a commonly known mechanism for disease. The variant was absent in 250800 control chromosomes (gnomAD). To our knowledge, no occurrence of c.632G>A in individuals affected with Usher Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. However, another variant resulting in the same amino acid change, c.633G>A (p.Trp211X) has been reported in the literature in at least one individual affected with Usher Syndrome (e.g. Bonnet_2016, PMID: 27460420). No submitters have cited clinical-significance assessments for c.632G>A to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Retinitis pigmentosa 39 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 26, 2023 | - - |
Rare genetic deafness Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Dec 23, 2013 | The Trp211X variant in USH2A has not been previously reported in individuals wit h hearing loss or in large population studies. This nonsense variant leads to a premature termination codon at position 211, which is predicted to lead to a tru ncated or absent protein. In summary, this variant meets our criteria to be clas sified as pathogenic (http://pcpgm.partners.org/LMM). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
Vest4
GERP RS
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at