chr1-201361314-C-T

Position:

chr1-201361314-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM1BS2

The NM_001276345.2(TNNT2):c.775G>A(p.Asp259Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00000991 in 1,614,080 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. D259D) has been classified as Benign.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000089 ( 0 hom. )

Consequence

TNNT2
NM_001276345.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:13

Conservation

PhyloP100: 5.93

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 Likely_benign. Variant got -2 ACMG points.

PM1

In a chain Troponin T, cardiac muscle (size 296) in uniprot entity TNNT2_HUMAN there are 88 pathogenic changes around while only 9 benign (91%) in NM_001276345.2

BS2

High AC in GnomAdExome4 at 13 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TNNT2	NM_001276345.2 linkuse as main transcript	c.775G>A	p.Asp259Asn	missense_variant	15/17	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.775G>A	p.Asp259Asn	missense_variant	15/17		NM_001276345.2	ENSP00000499593	A2	P45379-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152100

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000199

AC:

AN:

251474

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135910

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS 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:

0.00000889

AC:

AN:

1461862

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.000112

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152218

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74434

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000189

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 11, 2023	Identified as a variant of uncertain significance in cohorts of individuals with arrhythmia and cardiomyopathy in the literature; however, specific information was not provided about the number of individuals with the variant, their phenotype, or presence/absence of other variants (PMID: 23861362; 30847666; 30165862); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30847666, 30165862, 23861362) -
Uncertain significance, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 17, 2023	The TNNT2 c.745G>A; p.Asp249Asn variant (rs141805127) is reported in the literature in one individual with noncompaction cardiomyopathy, one individual from a cardiomyopathy cohort, and as a secondary variant from an exome cohort (Lu 2018, Ng 2013, van Lint 2019). This variant is also reported in ClinVar (Variation ID: 181630). This variant is found in the Admixed American population with an allele frequency of 0.01% (5/35426 alleles) in the Genome Aggregation Database. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.658). Due to limited information, the clinical significance of this variant is uncertain at this time. References: Lu C et al. Molecular analysis of inherited cardiomyopathy using next generation semiconductor sequencing technologies. J Transl Med. 2018 Aug 30;16(1):241. PMID: 30165862. Ng D et al. Interpreting secondary cardiac disease variants in an exome cohort. Circ Cardiovasc Genet. 2013 Aug;6(4):337-46. PMID: 23861362. van Lint FHM et al. Large next-generation sequencing gene panels in genetic heart disease: yield of pathogenic variants and variants of unknown significance. Neth Heart J. 2019 Jun;27(6):304-309. PMID: 30847666. -

Dilated cardiomyopathy 1D

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute of Immunology and Genetics Kaiserslautern	Mar 26, 2024	ACMG Criteria: PM2_P, PP3; Variant was found in heterozygous state -

Cardiomyopathy

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Nov 07, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 20, 2023	This missense variant replaces aspartic acid with asparagine at codon 249 of the TNNT2 protein. Computational prediction tools indicate that this variant's impact on protein structure and function is inconclusive. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in one individual affected with noncompaction cardiomyopathy (PMID: 30847666) and in one individual affected with an unspecified cardiomyopathy (PMID: 30165862). This variant has been identified in 6/282830 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Hypertrophic cardiomyopathy 2

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

Dilated cardiomyopathy 1D;C1861864:Hypertrophic cardiomyopathy 2;C2676271:Cardiomyopathy, familial restrictive, 3

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Aug 20, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 02, 2024	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 249 of the TNNT2 protein (p.Asp249Asn). This variant is present in population databases (rs141805127, gnomAD 0.01%). This missense change has been observed in individual(s) with TNNT2-related conditions (PMID: 30165862, 30847666). This variant is also known as p.Asp256Asn. ClinVar contains an entry for this variant (Variation ID: 181630). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TNNT2 protein function with a positive predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Cardiomyopathy, familial restrictive, 3

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Apr 11, 2023

- -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 21, 2021

The p.D249N variant (also known as c.745G>A), located in coding exon 13 of the TNNT2 gene, results from a G to A substitution at nucleotide position 745. The aspartic acid at codon 249 is replaced by asparagine, an amino acid with highly similar properties. This variant has been reported in one individual from a cardiomyopathy cohort and as a secondary cardiac variant in an exome cohort; however clinical details were limited (Ng D et al. Circ Cardiovasc Genet, 2013 Aug;6:337-46; Lu C et al. J Transl Med, 2018 08;16:241). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.55

CardioboostCm

Uncertain

0.13

BayesDel_addAF

Benign

-0.055

BayesDel_noAF

Uncertain

-0.060

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.96

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

Eigen

Uncertain

0.54

Eigen_PC

Uncertain

0.47

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.95

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

M_CAP

Pathogenic

0.56

MetaRNN

Uncertain

0.54

D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Uncertain

0.58

MutationAssessor

Uncertain

2.5

.;.;.;.;M;.;.;.;.;.;.

MutationTaster

Benign

1.0

D;D;D;D;D;D;D;D;D;D

PrimateAI

Uncertain

0.59

PROVEAN

Uncertain

-3.3

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

REVEL

Pathogenic

0.66

Sift

Uncertain

0.0010

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

Sift4G

Uncertain

0.0030

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

Polyphen

0.96

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

Vest4

0.54

MVP

0.95

MPC

0.77

ClinPred

0.84

GERP RS

3.7

Varity_R

0.65

gMVP

0.91

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

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