NM_020975.6:c.2307G>T

Variant names:

• chr10-43118395-G-T
• rs1800861
• NM_020975.6:c.2307G>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_020975.6(RET):​c.2307G>T​(p.Leu769Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.758 in 1,613,240 control chromosomes in the GnomAD database, including 467,321 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L769L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.78 (47440 hom., cov: 33)
  • Exomes 𝑓: 0.76 (419881 hom.)
• Consequence: RET NM_020975.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 1.28
• Publications: 162 publications found

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 Gene-Disease associations (from GenCC):

• familial medullary thyroid carcinoma

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, G2P
• multiple endocrine neoplasia type 2A

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen, G2P
• multiple endocrine neoplasia type 2B

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae), ClinGen
• pheochromocytoma

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• Hirschsprung disease, susceptibility to, 1

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• Haddad syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Hirschsprung disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• renal agenesis, unilateral

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• bilateral renal agenesis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• renal agenesis

  Inheritance: AR Classification: LIMITED Submitted by: G2P

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 10-43118395-G-T is Benign according to our data. Variant chr10-43118395-G-T is described in ClinVar as Benign. ClinVar VariationId is 167590.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.28 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.876 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020975.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RET	NM_020975.6	MANE Select	c.2307G>T	p.Leu769Leu	synonymous	Exon 13 of 20	NP_066124.1
	RET	NM_001406743.1		c.2307G>T	p.Leu769Leu	synonymous	Exon 13 of 21	NP_001393672.1
	RET	NM_001406744.1		c.2307G>T	p.Leu769Leu	synonymous	Exon 13 of 20	NP_001393673.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RET	ENST00000355710.8	TSL:5 MANE Select	c.2307G>T	p.Leu769Leu	synonymous	Exon 13 of 20	ENSP00000347942.3
	RET	ENST00000340058.6	TSL:1	c.2307G>T	p.Leu769Leu	synonymous	Exon 13 of 19	ENSP00000344798.4
	RET	ENST00000713926.1		c.2043G>T	p.Leu681Leu	synonymous	Exon 13 of 19	ENSP00000519223.1

Frequencies

GnomAD3 genomes AF: 0.785 AC: 119297 AN: 152042 Hom.: 47391 Cov.: 33

Gnomad AFR AF: 0.883

Gnomad AMI AF: 0.822

Gnomad AMR AF: 0.766

Gnomad ASJ AF: 0.711

Gnomad EAS AF: 0.495

Gnomad SAS AF: 0.620

Gnomad FIN AF: 0.782

Gnomad MID AF: 0.728

Gnomad NFE AF: 0.767

Gnomad OTH AF: 0.760

GnomAD2 exomes AF: 0.739 AC: 185430 AN: 250848 AF XY: 0.732

Gnomad AFR exome AF: 0.885

Gnomad AMR exome AF: 0.771

Gnomad ASJ exome AF: 0.714

Gnomad EAS exome AF: 0.506

Gnomad FIN exome AF: 0.767

Gnomad NFE exome AF: 0.769

Gnomad OTH exome AF: 0.753

GnomAD4 exome AF: 0.755 AC: 1103576 AN: 1461080 Hom.: 419881 Cov.: 47 AF XY: 0.751 AC XY: 545784 AN XY: 726868

African (AFR) AF: 0.883 AC: 29529 AN: 33460

American (AMR) AF: 0.769 AC: 34366 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.714 AC: 18652 AN: 26128

East Asian (EAS) AF: 0.484 AC: 19220 AN: 39684

South Asian (SAS) AF: 0.646 AC: 55697 AN: 86232

European-Finnish (FIN) AF: 0.761 AC: 40614 AN: 53362

Middle Eastern (MID) AF: 0.716 AC: 4127 AN: 5762

European-Non Finnish (NFE) AF: 0.771 AC: 856404 AN: 1111384

Other (OTH) AF: 0.745 AC: 44967 AN: 60358

GnomAD4 genome AF: 0.785 AC: 119408 AN: 152160 Hom.: 47440 Cov.: 33 AF XY: 0.782 AC XY: 58150 AN XY: 74378

African (AFR) AF: 0.883 AC: 36679 AN: 41534

American (AMR) AF: 0.766 AC: 11724 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.711 AC: 2468 AN: 3470

East Asian (EAS) AF: 0.495 AC: 2552 AN: 5154

South Asian (SAS) AF: 0.621 AC: 2986 AN: 4806

European-Finnish (FIN) AF: 0.782 AC: 8291 AN: 10602

Middle Eastern (MID) AF: 0.728 AC: 214 AN: 294

European-Non Finnish (NFE) AF: 0.767 AC: 52140 AN: 67974

Other (OTH) AF: 0.760 AC: 1606 AN: 2112

Alfa AF: 0.774 Hom.: 32988

Bravo AF: 0.792

Asia WGS AF: 0.591 AC: 2057 AN: 3478

EpiCase AF: 0.759

EpiControl AF: 0.766

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Oct 11, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Leu769Leu in exon 13 of RET: This variant is not expected to have clinical signi ficance because it has been identified in 23% (2018/8600) of European American c hromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/E VS/; dbSNP rs1800861).

Mar 23, 2016

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Multiple endocrine neoplasia type 2A Benign:2

Nov 07, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 26, 2025

Myriad Genetics, Inc.

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing.

Multiple endocrine neoplasia, type 2 Benign:2

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 28, 2019

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:2

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Multiple endocrine neoplasia type 2B Benign:1

Nov 07, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Pheochromocytoma Benign:1

Nov 07, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Hereditary cancer-predisposing syndrome Benign:1

Jul 10, 2025

GeneKor MSA

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	4.9
DANN	Benign	0.73
PhyloP100		1.3
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1800861; hg19: chr10-43613843; COSMIC: COSV60687116; COSMIC: COSV60687116;