9-114406535-G-T
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Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2BP4_ModerateBS1_Supporting
The NM_015404.4(WHRN):c.2056C>A(p.Pro686Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000235 in 1,613,640 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000024 ( 0 hom. )
Consequence
WHRN
NM_015404.4 missense
NM_015404.4 missense
Scores
3
5
11
Clinical Significance
Conservation
PhyloP100: 9.15
Genes affected
WHRN (HGNC:16361): (whirlin) This gene is thought to function in the organization and stabilization of sterocilia elongation and actin cystoskeletal assembly, based on studies of the related mouse gene. Mutations in this gene have been associated with autosomal recessive non-syndromic deafness and Usher Syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2016]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -1 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.12082654).
BS1
Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.000024 (35/1461296) while in subpopulation AMR AF= 0.000783 (35/44714). AF 95% confidence interval is 0.000578. There are 0 homozygotes in gnomad4_exome. There are 19 alleles in male gnomad4_exome subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| WHRN | NM_015404.4 | c.2056C>A | p.Pro686Thr | missense_variant | 9/12 | ENST00000362057.4 | NP_056219.3 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| WHRN | ENST00000362057.4 | c.2056C>A | p.Pro686Thr | missense_variant | 9/12 | 1 | NM_015404.4 | ENSP00000354623.3 |
Frequencies
GnomAD3 genomes 0.0000197 AC: 3AN: 152226Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000116 AC: 29AN: 249864Hom.: 0 AF XY: 0.000118 AC XY: 16AN XY: 135118
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GnomAD4 exome AF: 0.0000240 AC: 35AN: 1461296Hom.: 0 Cov.: 33 AF XY: 0.0000261 AC XY: 19AN XY: 726860
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GnomAD4 genome 0.0000197 AC: 3AN: 152344Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3AN XY: 74488
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Uncertain:2
| Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jan 19, 2016 | The p.Pro686Thr variant in DFNB31 has been previously identified by our laborato ry in 1 Hispanic individual with hearing loss; however, a variant on the remaini ng copy of DFNB31 has not been identified. It has been identified in 10/11564 La tino chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadins titute.org; dbSNP rs201690920). Although this variant has been seen in the gene ral population, its frequency is not high enough to rule out a pathogenic role. Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, the clinical signif icance of the p.Pro686Thr variant is uncertain. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia | May 05, 2015 | - - |
not provided Uncertain:2
| Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Nov 22, 2024 | 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 - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 24, 2022 | This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 686 of the WHRN protein (p.Pro686Thr). This variant is present in population databases (rs201690920, gnomAD 0.09%). This variant has not been reported in the literature in individuals affected with WHRN-related conditions. ClinVar contains an entry for this variant (Variation ID: 45666). 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: "Probably Damaging"; Align-GVGD: "Class C0"). 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. - |
Autosomal recessive nonsyndromic hearing loss 31 Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Usher syndrome type 2D Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Benign
.;.;T
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D
M_CAP
Benign
D
MetaRNN
Benign
T;T;T
MetaSVM
Benign
T
MutationAssessor
Uncertain
.;.;M
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N;N
REVEL
Benign
Sift
Pathogenic
D;D;D
Sift4G
Benign
T;T;T
Polyphen
1.0
.;D;D
Vest4
MutPred
0.17
.;.;Gain of phosphorylation at P686 (P = 0.0359);
MVP
MPC
0.55
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