rs146264950
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate
The NM_206933.4(USH2A):c.11815G>A(p.Glu3939Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000397 in 1,614,098 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_206933.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
USH2A | NM_206933.4 | c.11815G>A | p.Glu3939Lys | missense_variant | 61/72 | ENST00000307340.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
USH2A | ENST00000307340.8 | c.11815G>A | p.Glu3939Lys | missense_variant | 61/72 | 1 | NM_206933.4 | P1 | |
USH2A | ENST00000674083.1 | c.11815G>A | p.Glu3939Lys | missense_variant | 61/73 |
Frequencies
GnomAD3 genomes AF: 0.000447 AC: 68AN: 152098Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000492 AC: 123AN: 250102Hom.: 1 AF XY: 0.000539 AC XY: 73AN XY: 135314
GnomAD4 exome AF: 0.000392 AC: 573AN: 1461882Hom.: 1 Cov.: 33 AF XY: 0.000406 AC XY: 295AN XY: 727248
GnomAD4 genome AF: 0.000447 AC: 68AN: 152216Hom.: 0 Cov.: 32 AF XY: 0.000443 AC XY: 33AN XY: 74410
ClinVar
Submissions by phenotype
Usher syndrome type 2A Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jul 22, 2021 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Dec 27, 2019 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Pars Genome Lab | May 18, 2021 | - - |
not specified Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Apr 12, 2018 | Variant classified as Uncertain Significance - Favor Benign. The p.Glu3939Lys va riant in USH2A has been previously reported in 4 individuals with hearing loss a nd in 3 individuals with retinitis pigmentosa (Neveling 2012, Tajiguli 2016, Hae r-Wigman 2017, LMM data); however, none of these individuals had a second pathog enic variant identified in the USH2A gene. This variant has also been identified in 0.15% (15/10150) of Ashkenazi Jewish and 0.08% (97/125366) of European chrom osomes, including one homozygote, by the Genome Aggregation Database (gnomAD, ht tp://gnomad.broadinstitute.org; dbSNP rs146264950). Computational prediction too ls and conservation analysis do not provide strong support for or against an imp act to the protein. In summary, while the clinical significance of the p.Glu393 9Lys variant is uncertain, its frequency suggests that it is more likely to be b enign. ACMG/AMP Criteria applied: BS1_Supporting. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 15, 2023 | Variant summary: USH2A c.11815G>A (p.Glu3939Lys) results in a 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 benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00049 in 250102 control chromosomes in the gnomAD database, including 1 homozygote. This frequency is not higher than expected for a pathogenic variant in USH2A causing Usher Syndrome (0.00049 vs 0.011), allowing no conclusion about variant significance. c.11815G>A has been reported in the literature in individuals/families affected with retinitis pigmentosa and multifocal choroiditis (Neveling_2012, Tajiguli_2016, Haer-Wigman_2017, Jespersgaard_2019, McGowan_2020, Li_2021, Hufnagel_2022) but it has also been reported in unaffected homozygous individuals (gnomAD and PMID 34426522). In at least one of these reports, the variant was determined to not segregate in the affected family (Neveling_2012). These reports do 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. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Six classified as VUS, one submitter classified as Likely Benign. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Usher syndrome type 2A;C3151138:Retinitis pigmentosa 39 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | May 02, 2022 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Dec 23, 2016 | - - |
Retinitis pigmentosa 39 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Nov 16, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jul 22, 2021 | - - |
not provided Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 24, 2024 | - - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2024 | USH2A: BP4, BS1:Supporting - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at