chr10-43119560-A-G
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3_Moderate
The NM_020975.6(RET):c.2422A>G(p.Lys808Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00000249 in 1,608,920 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. K808N) 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_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RET | NM_020975.6 | c.2422A>G | p.Lys808Glu | missense_variant | 14/20 | ENST00000355710.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RET | ENST00000355710.8 | c.2422A>G | p.Lys808Glu | missense_variant | 14/20 | 5 | NM_020975.6 | P4 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152122Hom.: 0 Cov.: 34
GnomAD4 exome AF: 0.00000206 AC: 3AN: 1456798Hom.: 0 Cov.: 33 AF XY: 0.00000276 AC XY: 2AN XY: 724712
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152122Hom.: 0 Cov.: 34 AF XY: 0.0000135 AC XY: 1AN XY: 74296
ClinVar
Submissions by phenotype
Multiple endocrine neoplasia, type 2 Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Feb 24, 2023 | This missense variant replaces lysine with glutamic acid at codon 808 of the RET protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with medullary thyroid cancer (DOI: 10.1007/s00423-013-1109-y). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 30, 2023 | An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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. ClinVar contains an entry for this variant (Variation ID: 477350). This variant has not been reported in the literature in individuals affected with RET-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 808 of the RET protein (p.Lys808Glu). - |
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | May 11, 2023 | This missense variant replaces lysine with glutamic acid at codon 808 of the RET protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with medullary thyroid cancer (DOI: 10.1007/s00423-013-1109-y). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 21, 2023 | The p.K808E variant (also known as c.2422A>G), located in coding exon 14 of the RET gene, results from an A to G substitution at nucleotide position 2422. The lysine at codon 808 is replaced by glutamic acid, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at