rs771583281
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong
The NM_206933.4(USH2A):c.2167+5G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000328 in 1,613,608 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: 𝑓 0.000072 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000029 ( 0 hom. )
Consequence
USH2A
NM_206933.4 splice_region, intron
NM_206933.4 splice_region, intron
Scores
2
Splicing: ADA: 0.9999
2
Clinical Significance
Conservation
PhyloP100: 3.33
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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 10 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 1-216250898-C-T is Pathogenic according to our data. Variant chr1-216250898-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 552447.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-216250898-C-T is described in Lovd as [Likely_pathogenic]. Variant chr1-216250898-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| USH2A | ENST00000307340.8 | c.2167+5G>A | splice_region_variant, intron_variant | 1 | NM_206933.4 | ENSP00000305941.3 | ||||
| USH2A | ENST00000366942.3 | c.2167+5G>A | splice_region_variant, intron_variant | 1 | ENSP00000355909.3 | |||||
| USH2A | ENST00000674083.1 | c.2167+5G>A | splice_region_variant, intron_variant | ENSP00000501296.1 |
Frequencies
GnomAD3 genomes 0.0000723 AC: 11AN: 152106Hom.: 0 Cov.: 32
GnomAD3 genomes
AF:
AC:
11
AN:
152106
Hom.:
Cov.:
32
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.0000399 AC: 10AN: 250350Hom.: 0 AF XY: 0.00000739 AC XY: 1AN XY: 135302
GnomAD3 exomes
AF:
AC:
10
AN:
250350
Hom.:
AF XY:
AC XY:
1
AN XY:
135302
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.0000287 AC: 42AN: 1461502Hom.: 0 Cov.: 31 AF XY: 0.0000179 AC XY: 13AN XY: 727052
GnomAD4 exome
AF:
AC:
42
AN:
1461502
Hom.:
Cov.:
31
AF XY:
AC XY:
13
AN XY:
727052
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome 0.0000723 AC: 11AN: 152106Hom.: 0 Cov.: 32 AF XY: 0.0000673 AC XY: 5AN XY: 74306
GnomAD4 genome
AF:
AC:
11
AN:
152106
Hom.:
Cov.:
32
AF XY:
AC XY:
5
AN XY:
74306
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Alfa
AF:
Hom.:
Bravo
AF:
EpiCase
AF:
EpiControl
AF:
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:14
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Retinitis pigmentosa 39 Pathogenic:3
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 12, 2024 | - - |
| Pathogenic, criteria provided, single submitter | research | Ocular Genomics Institute, Massachusetts Eye and Ear | Apr 08, 2021 | The USH2A c.2167+5G>A variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PVS1, PM2, PM3. Based on this evidence we have classified this variant as Pathogenic. - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Apr 11, 2023 | - - |
Usher syndrome type 2A;C3151138:Retinitis pigmentosa 39 Pathogenic:2
| Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Jun 09, 2017 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Aug 12, 2021 | - - |
not provided Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 11, 2024 | This sequence change falls in intron 12 of the USH2A gene. It does not directly change the encoded amino acid sequence of the USH2A protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs771583281, gnomAD 0.01%). This variant has been observed in individuals with Usher syndrome 2 or retinitis pigmentosa (PMID: 12112664, 21151602, 24516651, 30190494). This variant is also known as IVS12+5G>A. ClinVar contains an entry for this variant (Variation ID: 552447). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 20497194). For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 22, 2024 | This variant is associated with the following publications: (PMID: 20497194, 25525159, 12112664, 25366773, 30190494, 24944099, 24516651, 23647439, 31589614, 33576794, 31456290, 34948090, 34781295, 32188678, 21151602) - |
Usher syndrome type 2A Pathogenic:2
| Likely pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Apr 11, 2023 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Dec 16, 2020 | - - |
Retinal dystrophy Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg | Jan 01, 2023 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Blueprint Genetics | May 22, 2019 | - - |
Usher syndrome Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 20, 2022 | Variant summary: USH2A c.2167+5G>A alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes a canonical 5' splicing donor site and one predicts an extreme weakening of this site. At least one publication reports experimental evidence that this variant affects mRNA splicing, resulting in both out-of frame skipping of exon 12 and an in-frame skipping of the exon with the use of an alternate splice site (Jaijo_2011). The variant allele was found at a frequency of 4e-05 in 250350 control chromosomes. This frequency is not higher than expected for a pathogenic variant in USH2A causing Usher Syndrome (4e-05 vs 0.011), allowing no conclusion about variant significance. c.2167+5G>A has been reported in the literature in multiple individuals affected with Usher Syndrome or Retinitis Pigmentosa (Avila-Fernandez_2010, Gao_2021, Jaijo_2011, Najera_2002, Columbo_2021), and some of these patients were reported as compound heterozygous with other (likely) pathogenic variants. These data indicate that the variant is very likely to be associated with disease. Eight submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 , and all laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
USH2A-related disorder Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Sep 13, 2024 | The USH2A c.2167+5G>A variant is predicted to interfere with splicing. This variant has been reported as pathogenic in patients with Usher syndrome and inherited retinal dystrophies, with functional studies demonstrating it results in exon skipping (Najera et al. 2002. PubMed ID: 12112664; Jaijo et al. 2011. PubMed ID: 20497194; González-Del Pozo et al 2018. PubMed ID: 30190494). This variant is reported in 0.014% of alleles in individuals of Latino descent in gnomAD. This variant is interpreted as pathogenic. - |
Retinitis pigmentosa Pathogenic:1
| Likely pathogenic, no assertion criteria provided | research | Sharon lab, Hadassah-Hebrew University Medical Center | Jun 23, 2019 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DL_spliceai
Position offset: 5
Find out detailed SpliceAI scores and Pangolin per-transcript scores at