10-43113655-G-C
Variant summary
The NM_020975.6(RET):c.1859G>C (p.Cys620Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. In-silico predictor (REVEL) classifies this variant as likely damaging/oncogenic. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. The affected nucleotide is highly conserved across species (PhyloP 100-way vertebrate score: 8.13). Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV001579533: Experimental studies have shown that this missense change affects RET function (PMID:9230192)." and additional evidence is available in ClinVar. A different missense at the same amino acid position has been reported as Pathogenic/Likely Pathogenic in ClinVar: p.C620R: Pathogenic (ClinVar VariationId 13915, 2 stars) Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.C620= (synonymous): Conflicting_classifications_of_pathogenicity (ClinVar VariationId 549782) This exact variant is curated in the UniProt human variants database as Uncertain Significance; it is also listed as a COSMIC curated somatic variant.
Frequency
Consequence
NM_020975.6 missense
Scores
Clinical Significance
Conservation
Publications
- familial medullary thyroid carcinomaInheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, G2P
- multiple endocrine neoplasia type 2AInheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen, G2P
- multiple endocrine neoplasia type 2BInheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), ClinGen, G2P
- pheochromocytomaInheritance: AD Classification: DEFINITIVE Submitted by: G2P
- Hirschsprung disease, susceptibility to, 1Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
- Haddad syndromeInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- Hirschsprung diseaseInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- renal agenesis, unilateralInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- bilateral renal agenesisInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
- renal agenesisInheritance: AR Classification: LIMITED Submitted by: G2P
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Classification according to ACMG Germline Pathogenicity v2019
Our verdict: Pathogenic. The variant received 26 points.
| Apply | Criterion Code & Title / Strength | Rationale / Clinical Context | |
|---|---|---|---|
| PS1Same amino acid change as known pathogenic | Same AA change, ≥2-star ClinVar pathogenic — very strong (PS1); ClinVar contains 1 P/LP entry with the same amino acid change (highest review level: 2 stars). | ||
| PS3Functional studies show damaging effect | Well-established functional study supports damaging effect (PS3); SCV001579533: Experimental studies have shown that this missense change affects RET function (PMID: 9230192).; SCV004930783: Functional studies indicate this variant impacts protein function [PMID: 9230192]. | ||
| PM1Mutational hot spot or critical domain | Missense neighbourhood hotspot (≥2 P/LP within ±8 AA, OR ≥ 5 vs. background) — PM1; In-domain: 0 pathogenic, 0 benign rare missense variants.; ±8 AA neighbourhood: 6 pathogenic, 2 benign (OR vs. background: 13.0). | ||
| PM2Absent/extremely low in population databases | Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD+AR) (base 0.0001, raised to 0.000122 by highest known P/LP ClinVar AF 0.000122) — PM2 moderate. | ||
| PM5Novel missense at known pathogenic residue | Different pathogenic missense at same AA residue in ClinVar (PM5); ClinVar contains a germline Pathogenic/Likely Pathogenic entry at the same amino acid position with a different amino acid change: p.C620R: Pathogenic (ClinVar VariationId 13915, 2 stars); Other variants at the same amino acid residue (not pathogenic): p.C620= (synonymous): Conflicting_classifications_of_pathogenicity (ClinVar VariationId 549782) | ||
| PP3Computational evidence supports damaging effect | Germline meta computational scorer (REVEL/MetaRNN/BayesDel) predicts damaging effect — strong evidence (PP3); Splicing verdict: not pathogenic.; Germline computational verdict: pathogenic (Strong). | ||
| PP5Reputable source reports pathogenic | ClinVar 2-star pathogenic — strong (PP5); ClinVar submissions overwhelmingly pathogenic (≥10 total, ≥80% P/LP, <10% B/LB) — strong (PP5, count-based); ClinVar germline classification: Pathogenic/Likely Pathogenic, 2 star(s). ClinVar submissions strongly and reliably favor pathogenicity (10/10 total P/LP). |
Variant Effect in Transcripts
Automated classification analysis was done for transcript: NM_020975.6. You can select a different transcript below to see updated classification assignments.
RefSeq Transcripts
| Sel. | Gene / Transcript | Tags | HGVSc / HGVSp | Effect | Exon rank | Protein / UniProt |
|---|---|---|---|---|---|---|
RET | MANE Select | c.1859G>C p.Cys620Ser | missense | Exon 10 of 20 | Prot: NP_066124.1 UniProt: | |
RET | c.1859G>C p.Cys620Ser | missense | Exon 10 of 21 | Prot: NP_001393672.1 UniProt: | ||
RET | c.1859G>C p.Cys620Ser | missense | Exon 10 of 20 | Prot: NP_001393673.1 |
Ensembl Transcripts
| Sel. | Gene / Transcript | Tags | HGVSc / HGVSp | Effect | Exon rank | Protein / UniProt |
|---|---|---|---|---|---|---|
RET | TSL:5MANE Select | c.1859G>C p.Cys620Ser | missense | Exon 10 of 20 | Prot: ENSP00000347942.3 UniProt: | |
RET | TSL:1 | c.1859G>C p.Cys620Ser | missense | Exon 10 of 19 | Prot: ENSP00000344798.4 UniProt: | |
RET | c.1730G>C p.Cys577Ser | missense | Exon 10 of 19 | Prot: ENSP00000519223.1 UniProt: |
Frequencies
Allele frequencies (AF), counts (AC/AN), homozygotes and coverage
| Source / population | AF | AC | Hom | AN | Coverage |
|---|---|---|---|---|---|
Global population databases 3 sources | |||||
GnomAD3 genomes | Cov:32 | ||||
GnomAD4 exome | Cov:31 | ||||
GnomAD4 genome | Cov:32 | ||||
Local & regional cohorts 1 source | |||||
ToMMo 61KJPN (+60KJPN MNV) | AF: 0.00000800 | AC:1 | Hom:0 | AN:122592 | |
ClinVar
Computational Scores
| Algorithm | Calibrated pred. | Score | Prediction |
|---|---|---|---|
AlphaGenome AVI | Pathogenic | 28 | |
AlphaMissense | Pathogenic | 0.98 | |
BayesDel_addAF | Pathogenic | 0.56 | D |
BayesDel_noAF | Pathogenic | 0.57 | |
CADD | Uncertain | 26 | |
DANN | Uncertain | 1.0 | |
DEOGEN2 | Pathogenic | 0.93 | D |
Eigen | Pathogenic | 0.79 | |
Eigen_PC | Pathogenic | 0.72 | |
FATHMM_MKL | Pathogenic | 0.99 | D |
FuncVEP CTI | Pathogenic | 1.0 | |
GPN-Star LLR | N/A | -7.9 | |
GPN-Star score | N/A | 7.9 | |
LIST_S2 | Benign | 0.84 | T |
M_CAP | Pathogenic | 0.68 | D |
MetaRNN | Pathogenic | 0.99 | D |
MetaSVM | Pathogenic | 1.1 | D |
Mutation Taster | N/A | 0/100 | disease causing (ClinVar) |
MutationAssessor | Uncertain | 2.7 | M |
PhyloP100 | Pathogenic | 8.1 | |
popEVE | Benign | -3.5 | |
PrimateAI | Uncertain | 0.54 | T |
PROVEAN | Pathogenic | -5.0 | D |
REVEL | Pathogenic | 0.94 | |
Sift | Benign | 0.040 | D |
Sift4G | Benign | 0.074 | T |
Varity_R | N/A | 0.87 | |
VESM-3B | Benign | -11 |
Splicing Scores
| Algorithm | Calibrated pred. | Score | Prediction |
|---|---|---|---|
Pangolin (max) | Benign | 0.0 | |
SpliceAI score (max) | Benign | 0.0 | Details are displayed if max score is > 0.2 |
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.