NM_020975.6:c.1216A>G
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate
The NM_020975.6(RET):āc.1216A>Gā(p.Ser406Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000161 in 1,613,720 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S406R) has been classified as Uncertain significance.
Frequency
Consequence
NM_020975.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
RET | NM_020975.6 | c.1216A>G | p.Ser406Gly | missense_variant | Exon 6 of 20 | ENST00000355710.8 | NP_066124.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152216Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251048Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135790
GnomAD4 exome AF: 0.0000157 AC: 23AN: 1461504Hom.: 0 Cov.: 33 AF XY: 0.0000151 AC XY: 11AN XY: 727084
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152216Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3AN XY: 74372
ClinVar
Submissions by phenotype
not provided Uncertain:2
Not observed at significant frequency in large population cohorts (gnomAD); 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 -
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Multiple endocrine neoplasia, type 2 Uncertain:1
This sequence change replaces serine, which is neutral and polar, with glycine, which is neutral and non-polar, at codon 406 of the RET protein (p.Ser406Gly). This variant is present in population databases (rs756532455, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with RET-related conditions. ClinVar contains an entry for this variant (Variation ID: 480783). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The glycine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. -
Hereditary cancer-predisposing syndrome Uncertain:1
The p.S406G variant (also known as c.1216A>G), located in coding exon 6 of the RET gene, results from an A to G substitution at nucleotide position 1216. The serine at codon 406 is replaced by glycine, an amino acid with similar properties. Based on data from gnomAD, the frequency for this variant is above the maximum credible frequency for a MEN2-causing variant in this gene based on internally established thresholds (Karczewski et al. Nature. 2020 May;581(7809):434-443; Whiffin et al. Genet Med. 2017 10;19:1151-1158). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the supporting evidence, the association of this alteration with Hirschsprung disease is unknown; however, the association of this alteration with MEN2 is unlikely. -
Ovarian cancer Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at