6-75890216-C-T
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate
The NM_004999.4(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 (★★).
Frequency
Consequence
NM_004999.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000106 AC: 16AN: 151468Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000116 AC: 29AN: 250952Hom.: 0 AF XY: 0.0000737 AC XY: 10AN XY: 135748
GnomAD4 exome AF: 0.000210 AC: 307AN: 1458518Hom.: 0 Cov.: 30 AF XY: 0.000185 AC XY: 134AN XY: 725876
GnomAD4 genome AF: 0.0000990 AC: 15AN: 151570Hom.: 0 Cov.: 33 AF XY: 0.000122 AC XY: 9AN XY: 73998
ClinVar
Submissions by phenotype
not provided Uncertain:4
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 -
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). This variant is present in population databases (rs200205409, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with MYO6-related conditions. ClinVar contains an entry for this variant (Variation ID: 357999). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt MYO6 protein function with a negative predictive value of 80%. 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. -
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. -
MYO6: PM2 -
not specified Uncertain:1
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
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
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
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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at