10-43124887-C-T

Position:

• chr10-43124887-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:32 O:2
• Conservation: PhyloP100: 1.17

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]

ACMG classification

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: {Likely_benign=5, not_provided=1, Benign=20, Uncertain_significance=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/exons	MANE	Protein	UniProt
RET	NM_020975.6	c.2944C>T	p.Arg982Cys	missense_variant	18/20	ENST00000355710.8	NP_066124.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RET	ENST00000355710.8	c.2944C>T	p.Arg982Cys	missense_variant	18/20	5	NM_020975.6	ENSP00000347942	P4

Frequencies

GnomAD3 genomes AF: 0.0165 AC: 2514 AN: 152186 Hom.: 30 Cov.: 33

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.: 78 AF XY: 0.0205 AC XY: 2785 AN XY: 135906

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.: 31 AF XY: 0.0171 AC XY: 12431 AN XY: 727090

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.: 30 Cov.: 33 AF XY: 0.0164 AC XY: 1224 AN XY: 74468

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.: 54

Bravo AF: 0.0169

TwinsUK AF: 0.0138 AC: 51

ALSPAC AF: 0.0156 AC: 60

ESP6500AA AF: 0.0159 AC: 70

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:2 Benign:32 Other:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:10 Other:1

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 23, 2019	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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 09, 2015	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). -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 23, 2016	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. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 23, 2014	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided Benign:5

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 21, 2017	- -
Benign, no assertion criteria provided	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jul 13, 2012	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 27, 2023	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	RET: BP4, BS1, BS2 -

Multiple endocrine neoplasia, type 2 Benign:3

Benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 05, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jun 09, 2022	- -

Hereditary cancer-predisposing syndrome Benign:3

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 24, 2014	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. -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Oct 15, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Vantari Genetics	Feb 04, 2016	- -

Multiple endocrine neoplasia type 2A Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Human Genetics, Inc, Center for Human Genetics, Inc	Nov 01, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Counsyl	Apr 05, 2016	- -

Multiple endocrine neoplasia type 2B Benign:2

Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Counsyl	Apr 05, 2016	- -

Multiple endocrine neoplasia Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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. -
Benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Apr 17, 2015	- -

Hirschsprung disease, susceptibility to, 1 Benign:1 Other:1

risk factor, no assertion criteria provided	literature only	OMIM	Aug 01, 1998	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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. -

Aganglionic megacolon Uncertain:1

Uncertain significance, no assertion criteria provided

research

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

Jan 01, 2013

- -

Breast-ovarian cancer, familial, susceptibility to, 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Department of Human Genetics, Hannover Medical School

Feb 01, 2022

- -

Pheochromocytoma Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

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. -

Renal hypodysplasia/aplasia 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

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. -

Familial medullary thyroid carcinoma Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Sep 24, 2015

- -

Malignant tumor of breast Benign:1

Benign, no assertion criteria provided

clinical testing

Center of Medical Genetics and Primary Health Care

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.82	D;.
Eigen	Benign	-0.081
Eigen_PC	Benign	-0.19
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.78	T;T
MetaRNN	Benign	0.0094	T;T
MetaSVM	Uncertain	-0.15	T
MutationAssessor	Benign	1.5	L;L
MutationTaster	Benign	0.95	D;D
PrimateAI	Benign	0.32	T
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	T
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

Other links and lift over

dbSNP: rs17158558; hg19: chr10-43620335; COSMIC: COSV60696488;