6-75890216-C-T
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Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate
The ENST00000369977.8(MYO6):c.2818C>T(p.Arg940Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0002 in 1,610,088 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R940H) has been classified as Uncertain significance.
Frequency
Genomes: 𝑓 0.000099 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00021 ( 0 hom. )
Consequence
MYO6
ENST00000369977.8 missense
ENST00000369977.8 missense
Scores
2
8
8
Clinical Significance
Conservation
PhyloP100: 4.89
Genes affected
MYO6 (HGNC:7605): (myosin VI) This gene encodes a reverse-direction motor protein that moves toward the minus end of actin filaments and plays a role in intracellular vesicle and organelle transport. The protein consists of a motor domain containing an ATP- and an actin-binding site and a globular tail which interacts with other proteins. This protein maintains the structural integrity of inner ear hair cells and mutations in this gene cause non-syndromic autosomal dominant and recessive hearing loss. Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Jul 2014]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -2 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.2171816).
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| MYO6 | NM_004999.4 | c.2818C>T | p.Arg940Cys | missense_variant | 26/35 | ENST00000369977.8 | NP_004990.3 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| MYO6 | ENST00000369977.8 | c.2818C>T | p.Arg940Cys | missense_variant | 26/35 | 1 | NM_004999.4 | ENSP00000358994 | A1 |
Frequencies
GnomAD3 genomes 0.000106 AC: 16AN: 151468Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000116 AC: 29AN: 250952Hom.: 0 AF XY: 0.0000737 AC XY: 10AN XY: 135748
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GnomAD4 exome AF: 0.000210 AC: 307AN: 1458518Hom.: 0 Cov.: 30 AF XY: 0.000185 AC XY: 134AN XY: 725876
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GnomAD4 genome 0.0000990 AC: 15AN: 151570Hom.: 0 Cov.: 33 AF XY: 0.000122 AC XY: 9AN XY: 73998
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:4
| Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Sep 30, 2022 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge - |
| Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Aug 01, 2024 | MYO6: PM2 - |
| Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Aug 25, 2017 | The p.Arg940Cys variant (rs200205409) has not been reported in the medical literature nor has it been previously identified in our laboratory. The p.Arg940Cys variant is listed in the Genome Aggregation Database (gnomAD) browser with an allele frequency of 0.023% in the non-Finnish European population (identified in 29 out of 126,304 chromosomes), and is classified as a variant of uncertain significance in ClinVar (Variant ID: 357999). The arginine at codon 940 is moderately conserved considering 13 species (Alamut software v2.9), and computational analyses predict conflicting effects of this variant on protein structure/function (SIFT: damaging, PolyPhen2: benign, MutationTaster: disease causing). Based on the available information, the clinical significance of the p.Arg940Cys variant cannot be determined with certainty. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Mar 09, 2022 | 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. 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: "Benign"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 357999). This variant has not been reported in the literature in individuals affected with MYO6-related conditions. This variant is present in population databases (rs200205409, gnomAD 0.02%). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 940 of the MYO6 protein (p.Arg940Cys). - |
not specified Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Sep 14, 2017 | The p.Arg940Cys variant in MYO6 has not been previously reported in individuals hearing loss, but has been identified in 29/ 126304 of European chromosomes by t he Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs200205409). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. Computational predi ction tools and conservation analyses suggest that this variant may impact the p rotein, though this information is not predictive enough to determine pathogenic ity. In summary, the clinical significance of the p.Arg940Cys variant is uncerta in. - |
Inborn genetic diseases Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 17, 2021 | The c.2818C>T (p.R940C) alteration is located in exon 26 (coding exon 25) of the MYO6 gene. This alteration results from a C to T substitution at nucleotide position 2818, causing the arginine (R) at amino acid position 940 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Autosomal recessive nonsyndromic hearing loss 37 Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 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. - |
Autosomal dominant nonsyndromic hearing loss 22 Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 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
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Benign
T;.;.;.;T;T;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;.;D;D;D;D;T
M_CAP
Benign
D
MetaRNN
Benign
T;T;T;T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Uncertain
.;M;M;M;.;.;.
MutationTaster
Benign
D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D;D;.;D;.;D
REVEL
Benign
Sift
Uncertain
D;D;D;.;D;.;D
Sift4G
Pathogenic
D;D;D;D;D;D;D
Polyphen
0.89, 0.97
.;P;D;P;.;.;.
Vest4
MVP
MPC
0.42
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
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