rs794727131
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2BP4_StrongBP6BP7
The NM_020975.6(RET):c.2454G>A(p.Glu818=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,459,880 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: not found (cov: 34)
Exomes 𝑓: 0.0000014 ( 0 hom. )
Consequence
RET
NM_020975.6 synonymous
NM_020975.6 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: 0.0370
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 Likely_benign. Variant got -4 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.52).
BP6
?
Variant 10-43119592-G-A is Benign according to our data. Variant chr10-43119592-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 194426.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=2}.
BP7
?
Synonymous conserved (PhyloP=0.037 with no splicing effect.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RET | NM_020975.6 | c.2454G>A | p.Glu818= | synonymous_variant | 14/20 | ENST00000355710.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RET | ENST00000355710.8 | c.2454G>A | p.Glu818= | synonymous_variant | 14/20 | 5 | NM_020975.6 | P4 |
Frequencies
GnomAD3 genomes ? Cov.: 34
GnomAD3 genomes
?
Cov.:
34
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1459880Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 726324
GnomAD4 exome
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2
AN:
1459880
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33
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0
AN XY:
726324
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GnomAD4 genome ? Cov.: 34
GnomAD4 genome
?
Cov.:
34
Bravo
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EpiCase
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EpiControl
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:3
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Hereditary cancer-predisposing syndrome Benign:2
Likely benign, criteria provided, single submitter | curation | Sema4, Sema4 | Jul 21, 2021 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 28, 2022 | This alteration is classified as likely 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. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jun 23, 2017 | - - |
MULTIPLE ENDOCRINE NEOPLASIA, TYPE IIA;C0025269:MULTIPLE ENDOCRINE NEOPLASIA, TYPE IIB;C0031511:Pheochromocytoma;C1275808:Congenital central hypoventilation;C1833921:Familial medullary thyroid carcinoma;C3888239:Hirschsprung disease, susceptibility to, 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Multiple endocrine neoplasia, type 2 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Oct 06, 2023 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
Cadd
Benign
Dann
Benign
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