NM_020975.6:c.2944C>T

Variant names:

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_020975.6(RET):c.2944C>T(p.Arg982Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0164 in 1,613,854 control chromosomes in the GnomAD database, including 372 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.017 ( 30 hom., cov: 33)

Exomes 𝑓: 0.016 ( 342 hom. )

Consequence

RET
NM_020975.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:33O:2

Conservation

PhyloP100: 1.17

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 Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009423137).

BP6

Variant 10-43124887-C-T is Benign according to our data. Variant chr10-43124887-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 13938.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=21, Likely_benign=5, not_provided=1}. Variant chr10-43124887-C-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0165 (2520/152304) while in subpopulation SAS AF= 0.0402 (194/4830). AF 95% confidence interval is 0.0355. There are 30 homozygotes in gnomad4. There are 1224 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 30 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RET	NM_020975.6 link	c.2944C>T	p.Arg982Cys	missense_variant	Exon 18 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.2944C>T	p.Arg982Cys	missense_variant	Exon 18 of 20	5	NM_020975.6	ENSP00000347942.3		P07949-1

Frequencies

GnomAD3 genomes

AF:

0.0165

AC:

2514

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0149

Gnomad AMI

AF:

0.00548

Gnomad AMR

AF:

0.0225

Gnomad ASJ

AF:

0.0248

Gnomad EAS

AF:

0.0156

Gnomad SAS

AF:

0.0397

Gnomad FIN

AF:

0.00528

Gnomad MID

AF:

0.0316

Gnomad NFE

AF:

0.0157

Gnomad OTH

AF:

0.0240

GnomAD3 exomes

AF:

0.0192

AC:

4838

AN:

251460

Hom.:

AF XY:

0.0205

AC XY:

2785

AN XY:

135906

show subpopulations

Gnomad AFR exome

AF:

0.0138

Gnomad AMR exome

AF:

0.0139

Gnomad ASJ exome

AF:

0.0336

Gnomad EAS exome

AF:

0.0141

Gnomad SAS exome

AF:

0.0431

Gnomad FIN exome

AF:

0.00684

Gnomad NFE exome

AF:

0.0171

Gnomad OTH exome

AF:

0.0200

GnomAD4 exome

AF:

0.0163

AC:

23888

AN:

1461550

Hom.:

342

Cov.:

AF XY:

0.0171

AC XY:

12431

AN XY:

727090

show subpopulations

Gnomad4 AFR exome

AF:

0.0152

Gnomad4 AMR exome

AF:

0.0147

Gnomad4 ASJ exome

AF:

0.0340

Gnomad4 EAS exome

AF:

0.00796

Gnomad4 SAS exome

AF:

0.0425

Gnomad4 FIN exome

AF:

0.00695

Gnomad4 NFE exome

AF:

0.0145

Gnomad4 OTH exome

AF:

0.0186

GnomAD4 genome

AF:

0.0165

AC:

2520

AN:

152304

Hom.:

Cov.:

AF XY:

0.0164

AC XY:

1224

AN XY:

74468

show subpopulations

Gnomad4 AFR

AF:

0.0149

Gnomad4 AMR

AF:

0.0225

Gnomad4 ASJ

AF:

0.0248

Gnomad4 EAS

AF:

0.0158

Gnomad4 SAS

AF:

0.0402

Gnomad4 FIN

AF:

0.00528

Gnomad4 NFE

AF:

0.0158

Gnomad4 OTH

AF:

0.0242

Alfa

AF:

0.0171

Hom.:

Bravo

AF:

0.0169

TwinsUK

AF:

0.0138

AC:

ALSPAC

AF:

0.0156

AC:

ESP6500AA

AF:

0.0159

AC:

ESP6500EA

AF:

0.0164

AC:

141

ExAC

AF:

0.0192

AC:

2335

Asia WGS

AF:

0.0370

AC:

129

AN:

3478

EpiCase

AF:

0.0190

EpiControl

AF:

0.0194

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:33Other:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:10Other:1

Oct 23, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 09, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Arg982Cys in exon 18 of RET: This variant is not expected to have clinical sig nificance because it is not located within the splice consensus sequence. It has been identified in 4% (666/16512) of South Asian chromosomes by the Exome Aggre gation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs17158558). -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

- -

Sep 23, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Dec 23, 2019

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: RET c.2944C>T (p.Arg982Cys) results in a non-conservative amino acid change located in the serine-threonine/tyrosine-protein kinase, catalytic domain (IPR001245) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.019 in 251460 control chromosomes in the gnomAD database, including 78 homozygotes. The observed variant frequency is approximately 1299 fold of the estimated maximal expected allele frequency for a pathogenic variant in RET causing Multiple Endocrine Neoplasia Type 2/Hirschsprung Disease phenotype (1.5e-05), strongly suggesting that the variant is benign. c.2944C>T has been reported in the early literature predating large control datasets in individuals reportedly affected with Multiple Endocrine Neoplasia Type 2/Hirschsprung Disease. These report(s) do not provide unequivocal conclusions about association of the variant with Multiple Endocrine Neoplasia Type 2/Hirschsprung Disease with no evidence supporting a damaging outcome in subsequent literature relating to this specific variant. At-least two co-occurrences with other pathogenic variant(s) have been reported (RET c.1852T>C, p.Cys618Arg; RET c.2410G>A, p.Val804Met), providing supporting evidence for a benign role (Mulligan_1994, and Lesueur_2005). At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant Pasini_1995. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (benign, n=7, likely benign, n=1, VUS, n=1). Based on the evidence outlined above, the variant was classified as benign. -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided

Benign:5

Jul 13, 2012

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: research

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

RET: BP4, BS1, BS2 -

Nov 22, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 21, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Multiple endocrine neoplasia, type 2

Benign:3

Jun 09, 2022

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 01, 2024

All of Us Research Program, National Institutes of Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome

Benign:3

Oct 15, 2020

Sema4, Sema4

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Feb 04, 2016

Vantari Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 24, 2014

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Multiple endocrine neoplasia type 2A

Uncertain:1Benign:1

Nov 01, 2016

Center for Human Genetics, Inc, Center for Human Genetics, Inc

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 05, 2016

Counsyl

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Multiple endocrine neoplasia type 2B

Benign:2

Apr 05, 2016

Counsyl

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Pheochromocytoma

Benign:2

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Feb 01, 2025

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Multiple endocrine neoplasia

Benign:2

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Apr 17, 2015

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hirschsprung disease, susceptibility to, 1

Benign:1Other:1

Aug 01, 1998

OMIM

Significance: risk factor

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Hirschsprung disease

Uncertain:1

Jan 01, 2013

Human Genomics Unit, Institute for molecular medicine Finland (FIMM)

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

- -

Breast-ovarian cancer, familial, susceptibility to, 1

Benign:1

Feb 01, 2022

Department of Human Genetics, Hannover Medical School

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Renal hypodysplasia/aplasia 1

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Familial medullary thyroid carcinoma

Benign:1

Sep 24, 2015

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Malignant tumor of breast

Benign:1

Center of Medical Genetics and Primary Health Care

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.27

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.82

D;.

Eigen

Benign

-0.081

Eigen_PC

Benign

-0.19

FATHMM_MKL

Benign

0.67

LIST_S2

Benign

0.78

T;T

MetaRNN

Benign

0.0094

T;T

MetaSVM

Uncertain

-0.15

MutationAssessor

Benign

1.5

L;L

PrimateAI

Benign

0.32

PROVEAN

Uncertain

-3.5

D;D

REVEL

Benign

0.28

Sift

Benign

0.058

T;D

Sift4G

Benign

0.072

T;T

Polyphen

1.0

D;D

Vest4

0.088

MPC

0.88

ClinPred

0.028

GERP RS

-0.30

Varity_R

0.51

gMVP

0.25

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