rs766809837
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Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PM2PP3
The NM_206933.4(USH2A):c.6908C>T(p.Ser2303Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00000682 in 1,613,514 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000062 ( 0 hom. )
Consequence
USH2A
NM_206933.4 missense
NM_206933.4 missense
Scores
5
7
7
Clinical Significance
Conservation
PhyloP100: 3.83
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 5 ACMG points.
PM1
?
In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_206933.4
PM2
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Very rare variant in population databases, with high coverage;
PP3
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MetaRNN computational evidence supports a deleterious effect, 0.781
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
USH2A | NM_206933.4 | c.6908C>T | p.Ser2303Phe | missense_variant | 36/72 | ENST00000307340.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
USH2A | ENST00000307340.8 | c.6908C>T | p.Ser2303Phe | missense_variant | 36/72 | 1 | NM_206933.4 | P1 | |
USH2A | ENST00000674083.1 | c.6908C>T | p.Ser2303Phe | missense_variant | 36/73 |
Frequencies
GnomAD3 genomes ? AF: 0.0000132 AC: 2AN: 152068Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000398 AC: 10AN: 251006Hom.: 0 AF XY: 0.0000369 AC XY: 5AN XY: 135638
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GnomAD4 exome AF: 0.00000616 AC: 9AN: 1461446Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5AN XY: 727022
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GnomAD4 genome ? AF: 0.0000132 AC: 2AN: 152068Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74260
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 07, 2024 | Variant summary: USH2A c.6908C>T (p.Ser2303Phe) results in a non-conservative amino acid change located in the Fibronectin type III domain (IPR003961) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-05 in 251006 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in USH2A causing Usher Syndrome (4e-05 vs 0.011), allowing no conclusion about variant significance. c.6908C>T has been reported in the literature in an individual affected with retinal dystrophy (Huang_2015). This report does not provide unequivocal conclusions about association of the variant with Usher Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 25356976). ClinVar contains an entry for this variant (Variation ID: 552851). Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Usher syndrome type 2A;C3151138:Retinitis pigmentosa 39 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Jul 12, 2017 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Feb 25, 2022 | This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 2303 of the USH2A protein (p.Ser2303Phe). This variant is present in population databases (rs766809837, gnomAD 0.05%). This missense change has been observed in individual(s) with inherited retinal dystrophy (PMID: 25356976). ClinVar contains an entry for this variant (Variation ID: 552851). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C25"). 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 | - - |
Usher syndrome type 2A 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
Uncertain
DANN
Uncertain
DEOGEN2
Benign
T
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D
MetaSVM
Uncertain
T
MutationAssessor
Uncertain
M
MutationTaster
Benign
D;D
PrimateAI
Benign
T
PROVEAN
Uncertain
N
REVEL
Uncertain
Sift
Uncertain
D
Sift4G
Pathogenic
D
Polyphen
D
Vest4
MutPred
Loss of methylation at R2305 (P = 0.2039);
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