chr10-43119736-C-T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6_Very_StrongBP7

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

Scores

7

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -3.05

Publications

0 publications found
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 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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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
RETNM_020975.6 linkc.2598C>T p.Ala866Ala synonymous_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
RETENST00000355710.8 linkc.2598C>T p.Ala866Ala synonymous_variant Exon 14 of 20 5 NM_020975.6 ENSP00000347942.3 P07949-1

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152146
Hom.:
0
Cov.:
34
show subpopulations
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
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 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
show subpopulations
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
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.514
Heterozygous variant carriers
0
1
2
2
3
4
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152146
Hom.:
0
Cov.:
34
AF XY:
0.0000269
AC XY:
2
AN XY:
74326
show subpopulations
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
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.475
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
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
LINK: link

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

Publications

Other links and lift over

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