rs149897775
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBS1_Supporting
The NM_015404.4(WHRN):c.2417C>T(p.Pro806Leu) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000758 in 1,610,500 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P806Q) has been classified as Benign.
Frequency
Consequence
NM_015404.4 missense, splice_region
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
WHRN | NM_015404.4 | c.2417C>T | p.Pro806Leu | missense_variant, splice_region_variant | 10/12 | ENST00000362057.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
WHRN | ENST00000362057.4 | c.2417C>T | p.Pro806Leu | missense_variant, splice_region_variant | 10/12 | 1 | NM_015404.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000355 AC: 54AN: 152136Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000964 AC: 24AN: 248840Hom.: 0 AF XY: 0.0000742 AC XY: 10AN XY: 134714
GnomAD4 exome AF: 0.0000459 AC: 67AN: 1458246Hom.: 0 Cov.: 32 AF XY: 0.0000400 AC XY: 29AN XY: 725584
GnomAD4 genome ? AF: 0.000361 AC: 55AN: 152254Hom.: 0 Cov.: 33 AF XY: 0.000322 AC XY: 24AN XY: 74442
ClinVar
Submissions by phenotype
not specified Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Mar 25, 2015 | The p.Pro806Leu variant in DFNB31 has not been previously reported in individual s with hearing loss, but has been identified in 0.16% (17/10380) of African chro mosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.or g; dbSNP rs149897775). Computational prediction tools and conservation analyses suggest that the p.Pro806Leu variant may impact the protein, though this informa tion is not predictive enough to determine pathogenicity. In summary, the clinic al significance of this variant is uncertain. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 11, 2024 | Variant summary: WHRN c.2417C>T (p.Pro806Leu) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 9.6e-05 in 248840 control chromosomes, predominantly at a frequency of 0.0015 within the African or African-American subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in WHRN causing Usher Syndrome (9.6e-05 vs 0.0038), allowing no conclusion about variant significance. c.2417C>T has been reported in the literature in an individual affected with non-syndromic hearing loss (Sloan-Heggen_2016). 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: 26969326). ClinVar contains an entry for this variant (Variation ID: 228562). Based on the evidence outlined above, the variant was classified as uncertain significance. - |
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | May 05, 2021 | Observed in published literature in a patient with hearing loss, described as c.1268 C>T, p.P423L using alternate nomenclature (Sloan-Heggen et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26969326) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 26, 2024 | This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 806 of the WHRN protein (p.Pro806Leu). This variant is present in population databases (rs149897775, gnomAD 0.1%). This missense change has been observed in individual(s) with early-onset hearing loss (PMID: 26969326). This variant is also known as c.1268C>T (p.Pro423Leu). ClinVar contains an entry for this variant (Variation ID: 228562). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at