rs377767402
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM1BP4BP6
The NM_020975.6(RET):c.1867G>A(p.Glu623Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000682 in 1,613,194 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000048 ( 0 hom. )
Consequence
RET
NM_020975.6 missense
NM_020975.6 missense
Scores
1
11
7
Clinical Significance
Conservation
PhyloP100: 5.31
Genes affected
RET (HGNC:9967): (ret proto-oncogene) This gene encodes a transmembrane receptor and member of the tyrosine protein kinase family of proteins. Binding of ligands such as GDNF (glial cell-line derived neurotrophic factor) and other related proteins to the encoded receptor stimulates receptor dimerization and activation of downstream signaling pathways that play a role in cell differentiation, growth, migration and survival. The encoded receptor is important in development of the nervous system, and the development of organs and tissues derived from the neural crest. This proto-oncogene can undergo oncogenic activation through both cytogenetic rearrangement and activating point mutations. Mutations in this gene are associated with Hirschsprung disease and central hypoventilation syndrome and have been identified in patients with renal agenesis. [provided by RefSeq, Sep 2017]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 0 ACMG points.
PM1
In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 14 uncertain in NM_020975.6
BP4
Computational evidence support a benign effect (MetaRNN=0.3009891).
BP6
Variant 10-43113663-G-A is Benign according to our data. Variant chr10-43113663-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 24906.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Benign=1, Likely_benign=1}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RET | NM_020975.6 | c.1867G>A | p.Glu623Lys | missense_variant | 10/20 | ENST00000355710.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RET | ENST00000355710.8 | c.1867G>A | p.Glu623Lys | missense_variant | 10/20 | 5 | NM_020975.6 | P4 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152134Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000241 AC: 6AN: 248886Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 134780
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GnomAD4 exome AF: 0.00000479 AC: 7AN: 1461060Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2AN XY: 726758
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GnomAD4 genome AF: 0.0000263 AC: 4AN: 152134Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74312
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Multiple endocrine neoplasia, type 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 28, 2024 | This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 623 of the RET protein (p.Glu623Lys). This variant is present in population databases (rs377767402, gnomAD 0.02%). This missense change has been observed in individual(s) with medullary thyroid cancer (PMID: 15858153). ClinVar contains an entry for this variant (Variation ID: 24906). 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. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jan 05, 2021 | Observed in a family with medullary thyroid carcinoma but did not segregate with disease, indicating that this variant is unlikely to be associated with increased risk for Multiple Endocrine Neoplasia type 2/Familial Medullary Thyroid Carcinoma (Ahmed 2005); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 9068588, 15858153, 16849421, 14633923, 32284345) - |
Multiple endocrine neoplasia type 2A Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
Hereditary cancer-predisposing syndrome Benign:1
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 29, 2016 | This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Uncertain
T;T;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D
M_CAP
Uncertain
D
MetaRNN
Benign
T;T;T
MetaSVM
Pathogenic
D
MutationAssessor
Uncertain
M;.;M
MutationTaster
Benign
D;D
PrimateAI
Benign
T
PROVEAN
Benign
N;N;N
REVEL
Uncertain
Sift
Benign
T;D;T
Sift4G
Benign
T;D;T
Polyphen
P;.;D
Vest4
MutPred
Gain of ubiquitination at E623 (P = 0.0155);.;Gain of ubiquitination at E623 (P = 0.0155);
MVP
MPC
ClinPred
T
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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