chr1-216196551-AC-A
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Variant summary
Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1PM2PP3_ModeratePP5_Very_Strong
The NM_206933.4(USH2A):c.4251+1del variant causes a splice donor change. The variant was absent in control chromosomes in GnomAD project. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: not found (cov: 32)
Consequence
USH2A
NM_206933.4 splice_donor
NM_206933.4 splice_donor
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 5.77
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 20 ACMG points.
PVS1
Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
PM2
Very rare variant in population databases, with high coverage;
PP3
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
Variant 1-216196551-AC-A is Pathogenic according to our data. Variant chr1-216196551-AC-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1069779.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
USH2A | NM_206933.4 | c.4251+1del | splice_donor_variant | ENST00000307340.8 | |||
USH2A-AS1 | XR_922596.4 | n.691+628del | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
USH2A | ENST00000307340.8 | c.4251+1del | splice_donor_variant | 1 | NM_206933.4 | P1 | |||
USH2A | ENST00000366942.3 | c.4251+1del | splice_donor_variant | 1 | |||||
USH2A-AS1 | ENST00000420867.1 | n.362+628del | intron_variant, non_coding_transcript_variant | 3 | |||||
USH2A | ENST00000674083.1 | c.4251+1del | splice_donor_variant |
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/Likely pathogenic
Submissions summary: Pathogenic:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Retinitis pigmentosa 39 Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Apr 11, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | DBGen Ocular Genomics | Jun 23, 2021 | - - |
Usher syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 21, 2023 | Variant summary: USH2A c.4251+1delG is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes a canonical 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 250690 control chromosomes (gnomAD). To our knowledge, no occurrence of c.4251+1delG in individuals affected with Usher Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Two ClinVar submitters have assessed the variant since 2014: both classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | May 20, 2020 | For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in USH2A are known to be pathogenic (PMID: 10729113, 10909849, 20507924, 25649381). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. This variant has not been reported in the literature in individuals with USH2A-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Gln1417Hisfs*15) in the USH2A gene. It is expected to result in an absent or disrupted protein product. - |
Usher syndrome type 2A Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Apr 11, 2023 | - - |
Computational scores
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Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DL_spliceai
Position offset: 2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
No publications associated with this variant yet.