chr10-43119736-C-T

Variant names:

• chr10-43119736-C-T
• rs202029768
• NM_020975.6:c.2598C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6_Very_Strong BP7

The NM_020975.6(RET):​c.2598C>T​(p.Ala866Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000682 in 1,613,092 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A866A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 34)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: RET NM_020975.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -3.05
• Publications: 0 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_addAF=-0.347274).
• BP6: Variant 10-43119736-C-T is Benign according to our data. Variant chr10-43119736-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 486318.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43119736-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 486318.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43119736-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 486318.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43119736-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 486318.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43119736-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 486318.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43119736-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 486318.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43119736-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 486318.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43119736-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 486318.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43119736-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 486318.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43119736-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 486318.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43119736-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 486318.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43119736-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 486318.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43119736-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 486318.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43119736-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 486318.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43119736-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 486318.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43119736-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 486318.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43119736-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 486318.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43119736-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 486318.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43119736-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 486318.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43119736-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 486318.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43119736-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 486318.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43119736-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 486318.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43119736-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 486318.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43119736-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 486318.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43119736-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 486318.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43119736-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 486318.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43119736-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 486318.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43119736-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 486318.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43119736-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 486318.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43119736-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 486318.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43119736-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 486318.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43119736-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 486318.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43119736-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 486318.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43119736-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 486318.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43119736-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 486318.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43119736-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 486318.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43119736-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 486318.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43119736-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 486318.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43119736-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 486318.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43119736-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 486318.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43119736-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 486318.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43119736-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 486318.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43119736-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 486318.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43119736-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 486318.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43119736-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 486318.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43119736-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 486318.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43119736-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 486318.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43119736-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 486318.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43119736-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 486318.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.05 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RET	NM_020975.6	c.2598C>T	p.Ala866Ala	synonymous_variant	Exon 14 of 20	ENST00000355710.8	NP_066124.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RET	ENST00000355710.8	c.2598C>T	p.Ala866Ala	synonymous_variant	Exon 14 of 20	5	NM_020975.6	ENSP00000347942.3

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152146 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000400 AC: 1 AN: 249946 AF XY: 0.00000739

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1460946 Hom.: 0 Cov.: 33 AF XY: 0.00000826 AC XY: 6 AN XY: 726820

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52648

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5742

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1111920

Other (OTH) AF: 0.00 AC: 0 AN: 60372

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152146 Hom.: 0 Cov.: 34 AF XY: 0.0000269 AC XY: 2 AN XY: 74326

African (AFR) AF: 0.0000241 AC: 1 AN: 41428

American (AMR) AF: 0.00 AC: 0 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68012

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000329 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Multiple endocrine neoplasia, type 2 Benign:2

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 28, 2023

All of Us Research Program, National Institutes of Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Multiple endocrine neoplasia type 2A Benign:1

Feb 27, 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. -

Hereditary cancer-predisposing syndrome Benign:1

Dec 22, 2016

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	0.23
DANN	Benign	0.43
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.023	N
PhyloP100		-3.1
Vest4		0.74
GERP RS		-11
Mutation Taster		=99/1	polymorphism

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: rs202029768; hg19: chr10-43615184; COSMIC: COSV100394540;