rs587783023
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PM2
The NM_206933.4(USH2A):āc.2414G>Cā(p.Gly805Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0000471 in 1,613,880 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (ā ā ). Synonymous variant affecting the same amino acid position (i.e. G805G) has been classified as Likely benign.
Frequency
Genomes: š 0.000026 ( 0 hom., cov: 32)
Exomes š: 0.000049 ( 0 hom. )
Consequence
USH2A
NM_206933.4 missense
NM_206933.4 missense
Scores
2
9
8
Clinical Significance
Conservation
PhyloP100: 3.70
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 Uncertain_significance. Variant got 4 ACMG points.
PM1
In a disulfide_bond (size 18) in uniprot entity USH2A_HUMAN there are 5 pathogenic changes around while only 1 benign (83%) in NM_206933.4
PM2
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
USH2A | NM_206933.4 | c.2414G>C | p.Gly805Ala | missense_variant | 13/72 | ENST00000307340.8 | |
USH2A | NM_007123.6 | c.2414G>C | p.Gly805Ala | missense_variant | 13/21 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
USH2A | ENST00000307340.8 | c.2414G>C | p.Gly805Ala | missense_variant | 13/72 | 1 | NM_206933.4 | P1 | |
USH2A | ENST00000366942.3 | c.2414G>C | p.Gly805Ala | missense_variant | 13/21 | 1 | |||
USH2A | ENST00000674083.1 | c.2414G>C | p.Gly805Ala | missense_variant | 13/73 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152098Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000917 AC: 23AN: 250734Hom.: 0 AF XY: 0.0000959 AC XY: 13AN XY: 135496
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GnomAD4 exome AF: 0.0000493 AC: 72AN: 1461782Hom.: 0 Cov.: 31 AF XY: 0.0000468 AC XY: 34AN XY: 727188
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GnomAD4 genome AF: 0.0000263 AC: 4AN: 152098Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74292
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:9
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Usher syndrome type 2A;C3151138:Retinitis pigmentosa 39 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Feb 09, 2017 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Usher syndrome type 2A Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Nov 04, 2023 | - - |
Leber congenital amaurosis Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Molecular Diagnostics Laboratory, Seoul National University Hospital | Sep 18, 2014 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Feb 27, 2022 | This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 805 of the USH2A protein (p.Gly805Ala). This variant is present in population databases (rs587783023, gnomAD 0.1%). This missense change has been observed in individual(s) with USH2A-related conditions (PMID: 25445212, 27057829, 33691693). ClinVar contains an entry for this variant (Variation ID: 156393). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Retinitis pigmentosa 39 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Nov 04, 2023 | - - |
Retinal dystrophy Uncertain:1
Uncertain significance, criteria provided, single submitter | research | Dept Of Ophthalmology, Nagoya University | Oct 01, 2023 | - - |
Retinitis pigmentosa Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Benign
DANN
Uncertain
DEOGEN2
Benign
T;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Benign
T;T
M_CAP
Benign
T
MetaRNN
Uncertain
D;D
MetaSVM
Benign
T
MutationAssessor
Uncertain
M;M
MutationTaster
Benign
D;D;D
PrimateAI
Benign
T
PROVEAN
Uncertain
D;D
REVEL
Uncertain
Sift
Pathogenic
D;D
Sift4G
Uncertain
D;T
Polyphen
D;D
Vest4
MutPred
Loss of loop (P = 0.1242);Loss of loop (P = 0.1242);
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
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