rs121912559
Variant summary
Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PS1_ModerateBP4_StrongBS1_SupportingBS2
The NM_004999.4(MYO6):c.647A>T(p.Glu216Val) variant causes a missense change. The variant allele was found at a frequency of 0.000191 in 1,606,212 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt.
Frequency
Consequence
NM_004999.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYO6 | NM_004999.4 | c.647A>T | p.Glu216Val | missense_variant | 8/35 | ENST00000369977.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYO6 | ENST00000369977.8 | c.647A>T | p.Glu216Val | missense_variant | 8/35 | 1 | NM_004999.4 | A1 |
Frequencies
GnomAD3 genomes ? AF: 0.000197 AC: 30AN: 152206Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000319 AC: 80AN: 250648Hom.: 1 AF XY: 0.000443 AC XY: 60AN XY: 135558
GnomAD4 exome AF: 0.000190 AC: 276AN: 1453888Hom.: 2 Cov.: 29 AF XY: 0.000264 AC XY: 191AN XY: 723908
GnomAD4 genome ? AF: 0.000197 AC: 30AN: 152324Hom.: 0 Cov.: 32 AF XY: 0.000322 AC XY: 24AN XY: 74494
ClinVar
Submissions by phenotype
not provided Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Aug 26, 2022 | The p.Glu216Val variant in MYO6 has been reported in homozygous state in one Pakistani individual with severe-to-profound hearing loss and was not identified in 540 ethnically matched chromosomes (Ahmed 2003). Although this information suggests a role for this variant, it is possible that the variant segregates with another variant that is causative for the hearing loss. Additional evidence, such as screening for this variant in a large ethnically-matched control population and functional studies, is needed to assume pathogenicity. Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the Glu216Val variant is uncertain. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jul 22, 2020 | This sequence change replaces glutamic acid with valine at codon 216 of the MYO6 protein (p.Glu216Val). The glutamic acid residue is highly conserved and there is a moderate physicochemical difference between glutamic acid and valine. This variant is present in population databases (rs121912559, ExAC 0.3%). This variant has been observed in individual(s) with autosomal recessive deafness (PMID: 12687499). ClinVar contains an entry for this variant (Variation ID: 8580). This variant has been reported to affect MYO6 protein function (PMID: 32143290). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Apr 14, 2023 | Observed in homozygous state in a patient with congenital sensorineural hearing loss in the literature (Ahmed et al., 2003), however, this individual was not screened for variants in other genes associated with hearing loss, and the variant was also observed in at least one homozygous individual in large population cohorts (gnomAD); Published functional studies are inconclusive regarding the functional impact of this variant (Oka et al., 2020); 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: 31250571, 29224747, 30245029, 32143290, 12687499) - |
Autosomal recessive nonsyndromic hearing loss 37 Pathogenic:1Uncertain:1
Pathogenic, no assertion criteria provided | literature only | OMIM | May 01, 2003 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Oct 27, 2016 | The MYO6 c.647A>T (p.Glu216Val) missense variant has been reported in at least one study in a homozygous state in one individual with hearing loss and in a heterozygous state in at least one unaffected family member (Ahmed et al. 2003). The p.Glu216Val variant was absent from 351 controls, but is reported at a frequency of 0.03398 in the Gujarati Indian in Houston, Texas population from the 1000 Genomes Project. This allele frequency is high but is consistent with the disease prevalence. Computational analyses of the p.Glu216Val variant by Butt et al. (2012) showed that the variant may affect protein stability and result in structural abnormalities that could affect binding properties. The evidence for this variant is limited. The p.Glu216Val variant is therefore classified as a variant of unknown significance but suspicious for pathogenicity for recessive nonsyndromic hearing loss. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
Autosomal dominant nonsyndromic hearing loss 22 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at