rs559922535
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2BP4_ModerateBP6
The NM_206933.4(USH2A):āc.8993C>Gā(p.Ser2998Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,613,930 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S2998P) has been classified as Uncertain significance.
Frequency
Consequence
NM_206933.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
USH2A | NM_206933.4 | c.8993C>G | p.Ser2998Cys | missense_variant | 45/72 | ENST00000307340.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
USH2A | ENST00000307340.8 | c.8993C>G | p.Ser2998Cys | missense_variant | 45/72 | 1 | NM_206933.4 | P1 | |
USH2A | ENST00000674083.1 | c.8993C>G | p.Ser2998Cys | missense_variant | 45/73 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152208Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251114Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135706
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461604Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 727108
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152326Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74472
ClinVar
Submissions by phenotype
Usher syndrome type 2A;C3151138:Retinitis pigmentosa 39 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Nov 26, 2017 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 07, 2022 | This sequence change replaces serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 2998 of the USH2A protein (p.Ser2998Cys). This variant is present in population databases (rs559922535, gnomAD 0.006%). 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: 166466). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The cysteine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Nov 06, 2013 | Ser2998Cys in Exon 45 of USH2A: This variant is not expected to have clinical si gnificance because the serine (Ser) residue at position 2998 is poorly conserved across species, with hedgehog, wallaby, and opossum having a cysteine (Cys) at this position. In addition, computational analyses (SIFT, PolyPhen2, and AlignGV GD) suggest that the variant may not impact the protein. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at