rs3730238

Positions:

chr1-201361301-T-C

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBA1

The NM_001276345.2(TNNT2):c.788A>G(p.Lys263Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0322 in 1,614,024 control chromosomes in the GnomAD database, including 2,370 homozygotes. 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. K263K) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.061 ( 558 hom., cov: 32)

Exomes 𝑓: 0.029 ( 1812 hom. )

Consequence

TNNT2
NM_001276345.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:23

Conservation

PhyloP100: 4.04

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:

TNNT2 (HGNC:):

TNNT2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 12 uncertain in NM_001276345.2

BP4

Computational evidence support a benign effect (MetaRNN=0.0016825795).

BP6

Variant 1-201361301-T-C is Benign according to our data. Variant chr1-201361301-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 43669.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-201361301-T-C is described in Lovd as [Benign]. Variant chr1-201361301-T-C is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.146 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.788A>G	p.Lys263Arg	missense_variant	15/17	ENST00000656932.1	NP_001263274.1	P45379-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNNT2	ENST00000656932.1 linkuse as main transcript	c.788A>G	p.Lys263Arg	missense_variant	15/17		NM_001276345.2	ENSP00000499593.1		P45379-1

Frequencies

GnomAD3 genomes

AF:

0.0613

AC:

9318

AN:

152076

Hom.:

557

Cov.:

show subpopulations

Gnomad AFR

AF:

0.149

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0257

Gnomad ASJ

AF:

0.0199

Gnomad EAS

AF:

0.0455

Gnomad SAS

AF:

0.154

Gnomad FIN

AF:

0.0520

Gnomad MID

AF:

0.0633

Gnomad NFE

AF:

0.0155

Gnomad OTH

AF:

0.0393

GnomAD3 exomes

AF:

0.0470

AC:

11810

AN:

251476

Hom.:

650

AF XY:

0.0495

AC XY:

6730

AN XY:

135914

show subpopulations

Gnomad AFR exome

AF:

0.154

Gnomad AMR exome

AF:

0.0206

Gnomad ASJ exome

AF:

0.0215

Gnomad EAS exome

AF:

0.0449

Gnomad SAS exome

AF:

0.145

Gnomad FIN exome

AF:

0.0523

Gnomad NFE exome

AF:

0.0151

Gnomad OTH exome

AF:

0.0428

GnomAD4 exome

AF:

0.0292

AC:

42719

AN:

1461830

Hom.:

1812

Cov.:

AF XY:

0.0322

AC XY:

23447

AN XY:

727222

show subpopulations

Gnomad4 AFR exome

AF:

0.160

Gnomad4 AMR exome

AF:

0.0217

Gnomad4 ASJ exome

AF:

0.0196

Gnomad4 EAS exome

AF:

0.0482

Gnomad4 SAS exome

AF:

0.141

Gnomad4 FIN exome

AF:

0.0559

Gnomad4 NFE exome

AF:

0.0147

Gnomad4 OTH exome

AF:

0.0369

GnomAD4 genome

AF:

0.0613

AC:

9326

AN:

152194

Hom.:

558

Cov.:

AF XY:

0.0641

AC XY:

4774

AN XY:

74420

show subpopulations

Gnomad4 AFR

AF:

0.149

Gnomad4 AMR

AF:

0.0257

Gnomad4 ASJ

AF:

0.0199

Gnomad4 EAS

AF:

0.0456

Gnomad4 SAS

AF:

0.154

Gnomad4 FIN

AF:

0.0520

Gnomad4 NFE

AF:

0.0155

Gnomad4 OTH

AF:

0.0398

Alfa

AF:

0.0243

Hom.:

251

Bravo

AF:

0.0607

TwinsUK

AF:

0.0151

AC:

ALSPAC

AF:

0.0174

AC:

ESP6500AA

AF:

0.149

AC:

656

ESP6500EA

AF:

0.0148

AC:

127

ExAC

AF:

0.0507

AC:

6159

Asia WGS

AF:

0.0920

AC:

318

AN:

3478

EpiCase

AF:

0.0137

EpiControl

AF:

0.0145

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:23

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 14, 2011	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, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 18, 2008	- -

Cardiomyopathy

Benign:3

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 15, 2018	- -
Benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Oct 01, 2024	- -
Benign, no assertion criteria provided	clinical testing	Cohesion Phenomics	Oct 10, 2022	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 24, 2016	Variant summary: The TNNT2 c.758A>G (p.Lys253Arg) variant involves the alteration of a conserved nucleotide. 3/3 in silico tools predict a benign outcome for this variant. This variant was found in 6169/122538 control chromosomes (378 homozygotes) at a frequency of 0.0503436, which is approximately 288 times the estimated maximal expected allele frequency of a pathogenic TNNT2 variant (0.000175), suggesting this variant is likely a benign polymorphism. In literature, this variant has been reported as a polymorphism found in HCM patients as well as healthy controls (Watkins_1995, Torricelli_2003, Garcia_Castro_2007, etc.). It has also been found to not cosegregate with disease in HCM families (Watkins_1995). In a mammalian two-hybrid assay, L253R mutant did not affect on interactions between TnT and TnI or TnT and TnC (Mogensen_2004). In addition, multiple clinical diagnostic laboratories/reputable databases have classified this variant as benign. Taken together, this variant is classified as Benign. -
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	-	- -

Dilated cardiomyopathy 1D

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Apr 11, 2023

- -

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

Likely benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Apr 11, 2023

- -

Primary familial hypertrophic cardiomyopathy

Benign:1

Benign, criteria provided, single submitter

research

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Jun 24, 2013

- -

Hypertrophic cardiomyopathy

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

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

Likely benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Apr 11, 2023

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 02, 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

AlphaMissense

Benign

0.084

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Uncertain

0.040

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.62

.;.;.;.;D;.;.;.;.;.;D

Eigen

Benign

-0.27

Eigen_PC

Benign

-0.14

FATHMM_MKL

Uncertain

0.78

LIST_S2

Benign

0.78

.;T;T;T;T;T;T;.;.;T;.

MetaRNN

Benign

0.0017

T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

1.9

.;.;.;.;L;.;.;.;.;.;.

PrimateAI

Benign

0.40

PROVEAN

Benign

-1.5

N;N;D;.;N;.;.;.;N;N;N

REVEL

Uncertain

0.33

Sift

Benign

0.12

T;T;D;.;D;.;.;.;T;T;T

Sift4G

Benign

0.86

T;T;T;T;T;T;T;T;T;T;.

Polyphen

0.0050

.;.;.;.;B;.;.;.;.;.;.

Vest4

0.14

MPC

0.42

ClinPred

0.021

GERP RS

2.6

Varity_R

0.25

gMVP

0.47

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