rs199672621
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Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PM2
The NM_206933.4(USH2A):āc.1556A>Gā(p.Gln519Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000601 in 1,613,774 control chromosomes in the GnomAD database, with no homozygous occurrence. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ā ).
Frequency
Genomes: š 0.000072 ( 0 hom., cov: 32)
Exomes š: 0.000059 ( 0 hom. )
Consequence
USH2A
NM_206933.4 missense
NM_206933.4 missense
Scores
1
4
14
Clinical Significance
Conservation
PhyloP100: 4.87
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 hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain 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.1556A>G | p.Gln519Arg | missense_variant | 9/72 | ENST00000307340.8 | |
USH2A | NM_007123.6 | c.1556A>G | p.Gln519Arg | missense_variant | 9/21 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
USH2A | ENST00000307340.8 | c.1556A>G | p.Gln519Arg | missense_variant | 9/72 | 1 | NM_206933.4 | P1 | |
USH2A | ENST00000366942.3 | c.1556A>G | p.Gln519Arg | missense_variant | 9/21 | 1 | |||
USH2A | ENST00000674083.1 | c.1556A>G | p.Gln519Arg | missense_variant | 9/73 |
Frequencies
GnomAD3 genomes ? AF: 0.0000723 AC: 11AN: 152184Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000359 AC: 9AN: 250942Hom.: 0 AF XY: 0.0000369 AC XY: 5AN XY: 135608
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GnomAD4 exome AF: 0.0000588 AC: 86AN: 1461590Hom.: 0 Cov.: 32 AF XY: 0.0000660 AC XY: 48AN XY: 727110
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GnomAD4 genome ? AF: 0.0000723 AC: 11AN: 152184Hom.: 0 Cov.: 32 AF XY: 0.0000942 AC XY: 7AN XY: 74340
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Feb 01, 2017 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Mar 31, 2022 | This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 519 of the USH2A protein (p.Gln519Arg). This variant is present in population databases (rs199672621, gnomAD 0.009%). This variant has not been reported in the literature in individuals affected with USH2A-related conditions. ClinVar contains an entry for this variant (Variation ID: 48469). 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 tolerated. 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. - |
Usher syndrome type 2A Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Nov 04, 2023 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Apr 06, 2020 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Aug 18, 2010 | Variant classified as Uncertain Significance - Favor Benign. The Gln519Arg varia nt in USH2A has not been reported in the literature but was identified in our la boratory in one indivudal with another clear etiology for hearing loss. This res idue is conserved in mammals; however, computational analyses (PolyPhen, SIFT, A lignGVGD) provide inconsistent predictions regarding the impact to the protein. It should be noted that this lab has only sequenced the USH2A gene in XXX indivi duals such that the full spectrum of benign variation has not yet been defined f or this gene, increasing the possibility that this may be a benign variant. In s ummary, the clinical significance of this variant cannot be determined with cert ainty at this time; however, based upon the arguments described above, we would lean towards a more likely benign role. - |
Usher syndrome type 2A;C3151138:Retinitis pigmentosa 39 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Mar 22, 2017 | - - |
Retinitis pigmentosa 39 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Nov 04, 2023 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Uncertain
DEOGEN2
Benign
T;.
Eigen
Benign
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Benign
T;T
M_CAP
Benign
D
MetaRNN
Uncertain
D;D
MetaSVM
Benign
T
MutationAssessor
Benign
L;L
MutationTaster
Benign
D;D;D
PrimateAI
Benign
T
PROVEAN
Benign
N;N
REVEL
Benign
Sift
Benign
T;T
Sift4G
Uncertain
T;T
Polyphen
P;B
Vest4
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