rs750228923
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_206933.4(USH2A):c.1214del(p.Asn405IlefsTer3) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000155 in 1,613,112 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. N405N) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_206933.4 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
USH2A | NM_206933.4 | c.1214del | p.Asn405IlefsTer3 | frameshift_variant | 7/72 | ENST00000307340.8 | |
USH2A | NM_007123.6 | c.1214del | p.Asn405IlefsTer3 | frameshift_variant | 7/21 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
USH2A | ENST00000307340.8 | c.1214del | p.Asn405IlefsTer3 | frameshift_variant | 7/72 | 1 | NM_206933.4 | P1 | |
USH2A | ENST00000366942.3 | c.1214del | p.Asn405IlefsTer3 | frameshift_variant | 7/21 | 1 | |||
USH2A | ENST00000674083.1 | c.1214del | p.Asn405IlefsTer3 | frameshift_variant | 7/73 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152094Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000801 AC: 2AN: 249788Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135190
GnomAD4 exome AF: 0.0000144 AC: 21AN: 1461018Hom.: 0 Cov.: 31 AF XY: 0.0000151 AC XY: 11AN XY: 726794
GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152094Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3AN XY: 74288
ClinVar
Submissions by phenotype
Usher syndrome type 2A Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jan 20, 2014 | The Asn405fs variant in USH2A has been reported in at least 5 individuals with Usher syndrome type II, including one homozygote and 3 compound heterozygotes (Bernal 2005; Schwartz 2005; Sandberg 2008, Garcia-Garcia 2011). This frameshift variant is predicted to alter the protein’s amino acid sequence beginning at position 405 and lead to a premature termination codon 3 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. This variant meets our criteria to be classified as pathogenic (http://pcpgm.partners.org/LMM). - |
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Nov 04, 2023 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Jul 30, 2020 | - - |
Retinitis pigmentosa 39 Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 21, 2024 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Nov 04, 2023 | - - |
Usher syndrome type 2A;C3151138:Retinitis pigmentosa 39 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | May 02, 2017 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 08, 2024 | This sequence change creates a premature translational stop signal (p.Asn405Ilefs*3) in the USH2A gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in USH2A are known to be pathogenic (PMID: 10729113, 10909849, 20507924, 25649381). This variant is present in population databases (rs750228923, gnomAD 0.002%). This premature translational stop signal has been observed in individuals with Usher syndrome (PMID: 15671307, 25404053). ClinVar contains an entry for this variant (Variation ID: 189250). For these reasons, this variant has been classified as Pathogenic. - |
Retinal dystrophy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Blueprint Genetics | Jun 12, 2019 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at