rs397517978
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1_ModeratePM2PP3_StrongPP5_Very_Strong
The NM_206933.4(USH2A):c.12067-2A>G variant causes a splice acceptor change. The variant allele was found at a frequency of 0.0000224 in 1,608,340 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Genomes: 𝑓 0.000014 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000023 ( 0 hom. )
Consequence
USH2A
NM_206933.4 splice_acceptor
NM_206933.4 splice_acceptor
Scores
5
1
1
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 6.49
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 16 ACMG points.
PVS1
?
Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.014542892 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
?
Variant 1-215680378-T-C is Pathogenic according to our data. Variant chr1-215680378-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 48390.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-215680378-T-C is described in Lovd as [Pathogenic]. Variant chr1-215680378-T-C is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
USH2A | NM_206933.4 | c.12067-2A>G | splice_acceptor_variant | ENST00000307340.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
USH2A | ENST00000307340.8 | c.12067-2A>G | splice_acceptor_variant | 1 | NM_206933.4 | P1 | |||
USH2A | ENST00000674083.1 | c.12067-2A>G | splice_acceptor_variant |
Frequencies
GnomAD3 genomes ? AF: 0.0000136 AC: 2AN: 146810Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000841 AC: 21AN: 249584Hom.: 0 AF XY: 0.0000444 AC XY: 6AN XY: 135074
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GnomAD4 exome AF: 0.0000233 AC: 34AN: 1461530Hom.: 0 Cov.: 32 AF XY: 0.0000220 AC XY: 16AN XY: 727086
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:16
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:5
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 04, 2023 | Canonical splice site variant expected to result in aberrant splicing, although in the absence of functional evidence the actual effect of this sequence change is unknown; This variant is associated with the following publications: (PMID: 32531858, 34315337, 25525159, 25404053, 28981474, 26850479, 29490346, 30190494, 31456290, 34426522, 31589614, 32037395, 18641288, 22004887, 34948090, 34148116, 35266249, 18452394) - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | May 10, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 25, 2024 | This sequence change affects an acceptor splice site in intron 61 of the USH2A gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in USH2A are known to be pathogenic (PMID: 10729113, 10909849, 20507924, 25649381). This variant is present in population databases (rs397517978, gnomAD 0.04%). Disruption of this splice site has been observed in individual(s) with Usher syndrome (PMID: 18452394, 22004887, 25404053, 28981474). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 48390). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Oct 01, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Oct 12, 2020 | - - |
Usher syndrome type 2A Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Oct 01, 2021 | NM_206933.2(USH2A):c.12067-2A>G is a canonical splice variant classified as pathogenic in the context of USH2A-related disorders. c.12067-2A>G has been observed in cases with relevant disease (PMID: 27460420, 18452394, 22004887). Functional assessments of this variant are not available in the literature. c.12067-2A>G has been observed in population frequency databases (gnomAD: AMR 0.04%). In summary, NM_206933.2(USH2A):c.12067-2A>G is a canonical splice variant in a gene where loss of function is a known mechanism of disease, is predicted to disrupt protein function, and has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. - |
Pathogenic, criteria provided, single submitter | clinical testing | 3billion | Sep 01, 2022 | The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.008%). Canonical splice site is predicted to alter splicing and result in a loss or disruption of normal protein function. Multiple pathogenic loss-of-function variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000048390 / 3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Apr 11, 2023 | - - |
Retinitis pigmentosa 39 Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Apr 11, 2023 | - - |
Pathogenic, criteria provided, single submitter | research | Ocular Genomics Institute, Massachusetts Eye and Ear | Apr 08, 2021 | The USH2A c.12067-2A>G 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, PP1, PP3. Based on this evidence we have classified this variant as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 16, 2023 | - - |
Usher syndrome type 2 Pathogenic:1
Pathogenic, no assertion criteria provided | research | Sharon lab, Hadassah-Hebrew University Medical Center | Jun 23, 2019 | - - |
Usher syndrome type 2A;C3151138:Retinitis pigmentosa 39 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Rare genetic deafness Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | May 13, 2013 | The 12067-2A>G variant in USH2A has been reported in five individuals with Usher syndrome type 2, one individual with autosomal recessive retinitis pigmentosa a nd one individual with congenital sensorineural hearing loss (Sandberg 2008, Aus lender 2008, Garcia-Garcia 2011, LMM unpublished data). Four of these probands w ere homozygous or compound heterozygous. Segregation of this variant with disea se was demonstrated in two affected family members (Auslender 2008). In addition , this variant occurs in the invariant region (+/- 1,2) of the splice consensus sequence and is predicted to cause altered splicing leading to an abnormal or ab sent protein. In summary, this variant meets our criteria to be classified as pa thogenic. - |
Retinal dystrophy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Blueprint Genetics | Jun 19, 2018 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
MutationTaster
Benign
D;D
GERP RS
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_AL_spliceai
Position offset: -2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at