dbSNP rs749421642: RET:p.Lys821Glu (chr10-43119599-A-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP3_Moderate

The NM_020975.6(RET):c.2461A>G(p.Lys821Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,460,260 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 (★★).

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

RET
NM_020975.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 9.28

Variant links:

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]

RET links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.855

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RET	NM_020975.6 link	c.2461A>G	p.Lys821Glu	missense_variant	Exon 14 of 20	ENST00000355710.8	NP_066124.1	P07949-1A0A024R7T2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RET	ENST00000355710.8 link	c.2461A>G	p.Lys821Glu	missense_variant	Exon 14 of 20	5	NM_020975.6	ENSP00000347942.3		P07949-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000403

AC:

AN:

248002

Hom.:

AF XY:

0.00

AC XY:

AN XY:

134958

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000897

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000411

AC:

AN:

1460260

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726512

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000540

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000282

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Multiple endocrine neoplasia, type 2

Uncertain:2

Aug 15, 2023

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces lysine with glutamic acid at codon 821 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 not been reported as a germline mutation in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/248002 chromosomes 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. -

Jan 12, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 821 of the RET protein (p.Lys821Glu). This variant is present in population databases (rs749421642, gnomAD 0.0009%). This missense change has been observed in individual(s) with clinical features of Hirschsprung‚Äôs disease (PMID: 31510104). ClinVar contains an entry for this variant (Variation ID: 229991). 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 disruptive. 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

Nov 27, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The RET c.2461A>G (p.Lys821Glu) variant has been reported in the published literature in an individual with medullary thyroid carcinoma and two reportedly healthy relatives (PMID: 31510104 (2019)). The frequency of this variant in the general population, 0.000004 (1/248002 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant. -

Hereditary cancer-predisposing syndrome

Uncertain:1

Jul 13, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.K821E variant (also known as c.2461A>G), located in coding exon 14 of the RET gene, results from an A to G substitution at nucleotide position 2461. The lysine at codon 821 is replaced by glutamic acid, an amino acid with similar properties. This variant was identified in one family from a MEN2 testing cohort (Elisei R et al. Genes (Basel), 2019 09;10). 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: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.44

BayesDel_addAF

Pathogenic

0.29

BayesDel_noAF

Pathogenic

0.17

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.76

D;.

Eigen

Uncertain

0.45

Eigen_PC

Uncertain

0.44

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.90

D;D

M_CAP

Uncertain

0.23

MetaRNN

Pathogenic

0.85

D;D

MetaSVM

Uncertain

0.52

MutationAssessor

Benign

1.1

L;L

PrimateAI

Uncertain

0.65

PROVEAN

Uncertain

-2.4

N;N

REVEL

Pathogenic

0.66

Sift

Uncertain

0.026

D;D

Sift4G

Benign

0.096

T;T

Polyphen

1.0

D;D

Vest4

0.75

MutPred

0.48

Loss of MoRF binding (P = 0.0031);Loss of MoRF binding (P = 0.0031);

MVP

0.93

MPC

0.80

ClinPred

0.88

GERP RS

5.4

Varity_R

0.78

gMVP

0.81

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over