rs3729547

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_001276345.2(TNNT2):​c.348C>T​(p.Ile116Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.714 in 1,613,718 control chromosomes in the GnomAD database, including 413,386 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.70 ( 37423 hom., cov: 31)
Exomes 𝑓: 0.72 ( 375963 hom. )

Consequence

TNNT2
NM_001276345.2 synonymous

Scores

2

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:22

Conservation

PhyloP100: 0.348
Variant links:
Genes affected
TNNT2 (HGNC:11949): (troponin T2, cardiac type) This gene encodes the cardiac isoform of troponin T. The encoded protein is the tropomyosin-binding subunit of the troponin complex, which is located on the thin filament of striated muscles and regulates muscle contraction in response to alterations in intracellular calcium ion concentration. Mutations in this gene have been associated with familial hypertrophic cardiomyopathy as well as with dilated cardiomyopathy. [provided by RefSeq, May 2022]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.32).
BP6
Variant 1-201365254-G-A is Benign according to our data. Variant chr1-201365254-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 43632.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-201365254-G-A is described in Lovd as [Benign]. Variant chr1-201365254-G-A is described in Lovd as [Likely_benign].
BP7
Synonymous conserved (PhyloP=0.348 with no splicing effect.
BA1
GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.793 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TNNT2NM_001276345.2 linkc.348C>T p.Ile116Ile synonymous_variant Exon 10 of 17 ENST00000656932.1 NP_001263274.1 P45379-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TNNT2ENST00000656932.1 linkc.348C>T p.Ile116Ile synonymous_variant Exon 10 of 17 NM_001276345.2 ENSP00000499593.1 P45379-1

Frequencies

GnomAD3 genomes
AF:
0.699
AC:
106151
AN:
151904
Hom.:
37406
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.622
Gnomad AMI
AF:
0.605
Gnomad AMR
AF:
0.754
Gnomad ASJ
AF:
0.782
Gnomad EAS
AF:
0.553
Gnomad SAS
AF:
0.815
Gnomad FIN
AF:
0.802
Gnomad MID
AF:
0.753
Gnomad NFE
AF:
0.716
Gnomad OTH
AF:
0.706
GnomAD3 exomes
AF:
0.723
AC:
181760
AN:
251482
Hom.:
66361
AF XY:
0.729
AC XY:
99110
AN XY:
135918
show subpopulations
Gnomad AFR exome
AF:
0.618
Gnomad AMR exome
AF:
0.766
Gnomad ASJ exome
AF:
0.772
Gnomad EAS exome
AF:
0.544
Gnomad SAS exome
AF:
0.817
Gnomad FIN exome
AF:
0.790
Gnomad NFE exome
AF:
0.710
Gnomad OTH exome
AF:
0.749
GnomAD4 exome
AF:
0.716
AC:
1046009
AN:
1461696
Hom.:
375963
Cov.:
60
AF XY:
0.720
AC XY:
523486
AN XY:
727164
show subpopulations
Gnomad4 AFR exome
AF:
0.619
Gnomad4 AMR exome
AF:
0.765
Gnomad4 ASJ exome
AF:
0.777
Gnomad4 EAS exome
AF:
0.575
Gnomad4 SAS exome
AF:
0.813
Gnomad4 FIN exome
AF:
0.791
Gnomad4 NFE exome
AF:
0.708
Gnomad4 OTH exome
AF:
0.724
GnomAD4 genome
AF:
0.699
AC:
106218
AN:
152022
Hom.:
37423
Cov.:
31
AF XY:
0.705
AC XY:
52359
AN XY:
74302
show subpopulations
Gnomad4 AFR
AF:
0.622
Gnomad4 AMR
AF:
0.754
Gnomad4 ASJ
AF:
0.782
Gnomad4 EAS
AF:
0.554
Gnomad4 SAS
AF:
0.814
Gnomad4 FIN
AF:
0.802
Gnomad4 NFE
AF:
0.716
Gnomad4 OTH
AF:
0.706
Alfa
AF:
0.714
Hom.:
90814
Bravo
AF:
0.686
Asia WGS
AF:
0.676
AC:
2353
AN:
3478
EpiCase
AF:
0.715
EpiControl
AF:
0.718

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:22
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:8
Jan 18, 2008
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Sep 25, 2012
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. -

-
Genome Diagnostics Laboratory, University Medical Center Utrecht
Significance: Benign
Review Status: no assertion criteria provided
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

- -

-
Clinical Genetics, Academic Medical Center
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

-
PreventionGenetics, part of Exact Sciences
Significance: Benign
Review Status: criteria provided, single submitter
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

- -

-
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Cardiomyopathy Benign:2
Mar 15, 2018
Color Diagnostics, LLC DBA Color Health
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Oct 10, 2022
Cohesion Phenomics
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

not provided Benign:2
-
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Breakthrough Genomics, Breakthrough Genomics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: not provided

- -

Hypertrophic cardiomyopathy Benign:2
Jun 14, 2016
Illumina Laboratory Services, Illumina
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Sep 27, 2022
Cohesion Phenomics
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Dilated cardiomyopathy 1D Benign:1
Sep 10, 2021
Genome-Nilou Lab
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Dilated Cardiomyopathy, Dominant Benign:1
Jun 14, 2016
Illumina Laboratory Services, Illumina
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Left ventricular noncompaction cardiomyopathy Benign:1
Jun 14, 2016
Illumina Laboratory Services, Illumina
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Cardiomyopathy, familial restrictive, 3 Benign:1
Sep 10, 2021
Genome-Nilou Lab
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Familial restrictive cardiomyopathy Benign:1
Jun 14, 2016
Illumina Laboratory Services, Illumina
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Hypertrophic cardiomyopathy 2 Benign:1
Sep 10, 2021
Genome-Nilou Lab
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Cardiovascular phenotype Benign:1
Jun 12, 2015
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. -

Dilated cardiomyopathy 1D;C1861864:Hypertrophic cardiomyopathy 2;C2676271:Cardiomyopathy, familial restrictive, 3 Benign:1
Feb 04, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.32
CADD
Benign
7.2
DANN
Benign
0.82

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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.

Other links and lift over

dbSNP: rs3729547; hg19: chr1-201334382; COSMIC: COSV52661393; COSMIC: COSV52661393; API