rs55966714
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Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 2P and 10B. PM2BP4_StrongBP6BP7BS1
The ENST00000362057.4(WHRN):c.2322C>T(p.Ser774=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000963 in 1,612,590 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00061 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0010 ( 1 hom. )
Consequence
WHRN
ENST00000362057.4 synonymous
ENST00000362057.4 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -0.546
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 Benign. Variant got -8 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.67).
BP6
Variant 9-114403992-G-A is Benign according to our data. Variant chr9-114403992-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 227292.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=4}. Variant chr9-114403992-G-A is described in Lovd as [Likely_benign].
BP7
Synonymous conserved (PhyloP=-0.546 with no splicing effect.
BS1
Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000611 (93/152322) while in subpopulation AMR AF= 0.00118 (18/15304). AF 95% confidence interval is 0.000795. There are 0 homozygotes in gnomad4. There are 47 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| WHRN | NM_015404.4 | c.2322C>T | p.Ser774= | synonymous_variant | 10/12 | ENST00000362057.4 | NP_056219.3 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| WHRN | ENST00000362057.4 | c.2322C>T | p.Ser774= | synonymous_variant | 10/12 | 1 | NM_015404.4 | ENSP00000354623 | P1 |
Frequencies
GnomAD3 genomes 0.000611 AC: 93AN: 152204Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000555 AC: 139AN: 250276Hom.: 0 AF XY: 0.000554 AC XY: 75AN XY: 135344
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GnomAD4 exome AF: 0.00100 AC: 1460AN: 1460268Hom.: 1 Cov.: 36 AF XY: 0.000947 AC XY: 688AN XY: 726498
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GnomAD4 genome 0.000611 AC: 93AN: 152322Hom.: 0 Cov.: 33 AF XY: 0.000631 AC XY: 47AN XY: 74474
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:4
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Benign:3
| Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 16, 2024 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | Apr 14, 2020 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Feb 04, 2021 | - - |
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. - |
not specified Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Oct 26, 2017 | p.Ser774Ser in Exon 10 of WHRN: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue, is not located withi n the splice consensus sequence, and has been identified in 0.1% (120/126604) of European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad. broadinstitute.org/; dbSNP rs55966714). - |
Computational scores
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Name
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
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