rs780779563
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_206933.4(USH2A):c.545_546delAA(p.Lys182ArgfsTer33) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,098 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. K182K) 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
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
USH2A | ENST00000307340.8 | c.545_546delAA | p.Lys182ArgfsTer33 | frameshift_variant | Exon 3 of 72 | 1 | NM_206933.4 | ENSP00000305941.3 | ||
USH2A | ENST00000366942.3 | c.545_546delAA | p.Lys182ArgfsTer33 | frameshift_variant | Exon 3 of 21 | 1 | ENSP00000355909.3 | |||
USH2A | ENST00000674083.1 | c.545_546delAA | p.Lys182ArgfsTer33 | frameshift_variant | Exon 3 of 73 | ENSP00000501296.1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.00000399 AC: 1AN: 250896Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135594
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461098Hom.: 0 AF XY: 0.00000275 AC XY: 2AN XY: 726850
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:2
The c.545_546delAA variant in the USH2A gene has been reported previously in association with autosomal recessive Usher syndrome type II (Sayedahmadi et al., 2004; Hartel et al., 2016). In addition, the c.545_546delAA variant has been reported in an individual with retinitis pigmentosa who also had another frameshift variant in the USH2A gene (Sandberg et al., 2008). The c.545_546delAA variant causes a frameshift starting with codon Lysine 182, changes this amino acid to an Arginine residue, and creates a premature Stop codon at position 33 of the new reading frame, denoted p.Lys182ArgfsX33. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.545_546delAA variant is not observed in large population cohorts (Lek et al., 2016). We interpret c.545_546delAA as a pathogenic variant. -
This sequence change creates a premature translational stop signal (p.Lys182Argfs*33) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with clinical features of Usher syndrome type II (PMID: 15325563, 18273898, 27318125). ClinVar contains an entry for this variant (Variation ID: 556324). For these reasons, this variant has been classified as Pathogenic. -
Retinitis pigmentosa 39 Pathogenic:2
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Usher syndrome type 2A Pathogenic:2
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Usher syndrome type 2A;C3151138:Retinitis pigmentosa 39 Pathogenic:1
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Retinal dystrophy Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at