rs3729547

Positions:

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.Ile116=) 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

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]

TNNT2 links:

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/exons	MANE	Protein	UniProt
TNNT2	NM_001276345.2 linkuse as main transcript	c.348C>T	p.Ile116=	synonymous_variant	10/17	ENST00000656932.1	NP_001263274.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNNT2	ENST00000656932.1 linkuse as main transcript	c.348C>T	p.Ile116=	synonymous_variant	10/17		NM_001276345.2	ENSP00000499593	A2	P45379-1

Frequencies

GnomAD3 genomes

AF:

0.699

AC:

106151

AN:

151904

Hom.:

37406

Cov.:

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.:

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.:

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

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 18, 2008	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 25, 2012	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	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Cardiomyopathy

Benign:2

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 15, 2018	- -
Benign, no assertion criteria provided	clinical testing	Cohesion Phenomics	Oct 10, 2022	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	-	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Hypertrophic cardiomyopathy

Benign:2

Benign, no assertion criteria provided	clinical testing	Cohesion Phenomics	Sep 27, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

Dilated cardiomyopathy 1D

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 10, 2021

- -

Dilated Cardiomyopathy, Dominant

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Left ventricular noncompaction cardiomyopathy

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Cardiomyopathy, familial restrictive, 3

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 10, 2021

- -

Familial restrictive cardiomyopathy

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Hypertrophic cardiomyopathy 2

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 10, 2021

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 12, 2015

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over