rs141943290
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PM2
The NM_206933.4(USH2A):c.12625G>A(p.Glu4209Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000421 in 1,613,994 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
USH2A | NM_206933.4 | c.12625G>A | p.Glu4209Lys | missense_variant | 63/72 | ENST00000307340.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
USH2A | ENST00000307340.8 | c.12625G>A | p.Glu4209Lys | missense_variant | 63/72 | 1 | NM_206933.4 | P1 | |
USH2A | ENST00000674083.1 | c.12625G>A | p.Glu4209Lys | missense_variant | 63/73 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152186Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000682 AC: 17AN: 249330Hom.: 0 AF XY: 0.0000667 AC XY: 9AN XY: 134886
GnomAD4 exome AF: 0.0000451 AC: 66AN: 1461808Hom.: 0 Cov.: 82 AF XY: 0.0000550 AC XY: 40AN XY: 727196
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152186Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74342
ClinVar
Submissions by phenotype
not provided Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Apr 15, 2022 | In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Dec 02, 2023 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Oct 06, 2016 | Variant classified as Uncertain Significance - Favor Benign. The p.Glu4209Lys va riant in USH2A has not been previously reported in individuals with hearing loss or Usher syndrome. It has been identified in 12/66294 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs 141943290); however, this frequency is not high enough to rule out a pathogenic role. The glutamic acid residue (Glu) at position 4209 is not conserved across species, with two mammals (prairie vole and golden hamster) having a lysine (Lys ) at this position. Additional computational predictions suggest that this varia nt may not impact the protein. In summary, while the clinical significance of th is variant is uncertain, these data suggest that it is more likely to be benign. - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 25, 2022 | The c.12625G>A (p.E4209K) alteration is located in exon 63 (coding exon 62) of the USH2A gene. This alteration results from a G to A substitution at nucleotide position 12625, causing the glutamic acid (E) at amino acid position 4209 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Usher syndrome type 2A Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Nov 11, 2019 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at