rs1553327452
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_206933.4(USH2A):c.1803del(p.Gly602GlufsTer34) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. G601G) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Consequence
USH2A
NM_206933.4 frameshift
NM_206933.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: -0.633
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 12 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 1-216292211-CT-C is Pathogenic according to our data. Variant chr1-216292211-CT-C is described in ClinVar as [Pathogenic]. Clinvar id is 503555.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-216292211-CT-C is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
USH2A | NM_206933.4 | c.1803del | p.Gly602GlufsTer34 | frameshift_variant | 10/72 | ENST00000307340.8 | |
USH2A | NM_007123.6 | c.1803del | p.Gly602GlufsTer34 | frameshift_variant | 10/21 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
USH2A | ENST00000307340.8 | c.1803del | p.Gly602GlufsTer34 | frameshift_variant | 10/72 | 1 | NM_206933.4 | P1 | |
USH2A | ENST00000366942.3 | c.1803del | p.Gly602GlufsTer34 | frameshift_variant | 10/21 | 1 | |||
USH2A | ENST00000674083.1 | c.1803del | p.Gly602GlufsTer34 | frameshift_variant | 10/73 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Usher syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Mar 07, 2018 | The p.Gly602fs variant in USH2A has been identified by our laboratory in 1 individual with Usher syndrome who carried a second pathogenic variant in the USH2A gene. It was absent from large population studies. This variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at position 602 and leads to a premature termination codon 34 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the USH2A gene is an established disease mechanism in Usher syndrome. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Usher syndrome. ACMG/AMP Criteria applied: PVS1; PM2, PM3. - |
Computational scores
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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