rs397516447

chr1-201368189-C-Gchr1-201368189-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM1BP4_ModerateBS2

The NM_001276345.2(TNNT2):c.136G>C(p.Ala46Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000173 in 1,614,042 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000015 ( 0 hom. )

Consequence

TNNT2
NM_001276345.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:9B:2

Conservation

PhyloP100: 2.47

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 -4 ACMG points.

PM1

In a chain Troponin T, cardiac muscle (size 296) in uniprot entity TNNT2_HUMAN there are 174 pathogenic changes around while only 18 benign (91%) in NM_001276345.2

BP4

Computational evidence support a benign effect (MetaRNN=0.0937376).

BS2

High AC in GnomAd at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNNT2	NM_001276345.2 linkuse as main transcript	c.136G>C	p.Ala46Pro	missense_variant	6/17	ENST00000656932.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNNT2	ENST00000656932.1 linkuse as main transcript	c.136G>C	p.Ala46Pro	missense_variant	6/17		NM_001276345.2	A2	P45379-1

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152196

Hom.:

Cov.:

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:

0.00104

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000318

AC:

AN:

251454

Hom.:

AF XY:

0.0000441

AC XY:

AN XY:

135906

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 SAS exome

AF:

0.000261

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000150

AC:

AN:

1461846

Hom.:

Cov.:

AF XY:

0.0000234

AC XY:

AN XY:

727230

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000220

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152196

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74352

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00104

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.0000494

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:9Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

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

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jul 08, 2022	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. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on TNNT2 function (PMID: 30565988, 33025817). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 43612). This variant is also known as A46P. This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 27532257). This variant is present in population databases (rs397516447, gnomAD 0.03%). This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 36 of the TNNT2 protein (p.Ala36Pro). -
Uncertain significance, criteria provided, single submitter	clinical testing	New York Genome Center	Aug 20, 2021	The c.136G>C (p.Ala46Pro) variant identified in the TNNT2 gene substitutes a moderately conserved Alanine for Proline at amino acid 46/299 (exon6/17). This variant is found with low frequency in gnomAD(v3.1.1) (6 heterozygotes, 0 homozygotes; allele frequency:3.94e-5) suggesting it is not a common benign variant in the populations represented in that database. In silico algorithms predict this variant to be Tolerated (SIFT; score:0.298) and Benign (REVEL; score:0.423) to the function of the canonical transcript. This variant is reported as a Variant of Uncertain Significance in ClinVar (VarID:43612) and has been reported in an individual in the literature with Hypertrophic Cardiomyopathy (listed as c.106G>C, p.Ala36Pro as annotated from transcript NM_001001430.2; [Supp Table S1B,PMID:27532257]). This variant is not within a mapped domain of TNNT2, but is located within a region of compositional bias of acid residues (UniProtKB:P45379). The c.136G>C (p.Ala46Pro) variant identified in the TNNT2 gene is reported as a Variant of Uncertain Significance. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 10, 2011

The Ala36Pro variant has not been reported in the literature. It has been detec ted by our laboratory in one Asian patient with HCM secondary to Pompe disease. It should be noted that this lab has only sequenced the TNNT2 in 162 Asian indi viduals and no Asian healthy controls. In addition, healthy control information is unavailable from either public databases or scientific literature, such that the full spectrum of benign variation has not yet been defined for this populati on. Future analysis could reveal that the Ala36Pro variant is common and therefo re unlikely to be pathogenic. In addition, alanine (Ala) at position 36 is locat ed in a less well conserved part of the TNNT2 protein, which may indicate that a change would be tolerated. In summary, the clinical significance of this varia nt cannot be determined without further studies. -

Dilated cardiomyopathy 1D

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Nov 04, 2023

- -

Cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Nov 02, 2023

This missense variant replaces alanine with proline at codon 36 of the TNNT2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). A functional study showed similar transcript expression as WT controls (PMID: 33025817). This variant has been reported in an individual affected with hypertrophic cardiomyopathy (PMID: 27532257). This variant has been identified in 8/251454 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. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Mar 13, 2023

Identified in a patient with hypertrophic cardiomyopathy (HCM) in published literature (Walsh et al., 2017); In silico analysis supports that this missense variant does not alter protein structure/function; Published functional studies suggest normal protein function (Pettinato et al., 2020); This variant is associated with the following publications: (PMID: 30645170, 30565988, 33025817, 27532257) -

Cardiomyopathy, familial restrictive, 3

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Nov 04, 2023

- -

Hypertrophic cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Agnes Ginges Centre for Molecular Cardiology, Centenary Institute

Apr 18, 2018

This variant has been identified as part of our research program. Refer to the 'condition' field for the phenotype of the proband(s) identified with this variant. For further information please feel free to contact us. -

Hypertrophic cardiomyopathy 2

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Nov 04, 2023

- -

Primary familial hypertrophic cardiomyopathy

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Blueprint Genetics

Oct 30, 2014

- -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 03, 2023

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

AlphaMissense

Benign

0.091

CardioboostCm

Benign

0.043

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.090

Cadd

Benign

Dann

Benign

0.97

Eigen

Benign

-0.67

Eigen_PC

Benign

-0.57

FATHMM_MKL

Uncertain

0.77

M_CAP

Pathogenic

0.34

MetaRNN

Benign

0.094

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

MetaSVM

Uncertain

0.76

MutationTaster

Benign

0.50

D;N;N;N;N;N;N;N;N;N

PrimateAI

Benign

0.44

PROVEAN

Benign

0.47

N;N;.;.;.;.;N;N;N;N;N;N

REVEL

Uncertain

0.42

Sift

Benign

0.26

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

Sift4G

Benign

0.28

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

Polyphen

0.0

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

Vest4

0.20

MutPred

0.17

.;.;.;Gain of glycosylation at A46 (P = 0.08);Gain of glycosylation at A46 (P = 0.08);.;Gain of glycosylation at A46 (P = 0.08);.;.;Gain of glycosylation at A46 (P = 0.08);.;.;

MVP

0.86

MPC

0.66

ClinPred

0.061

GERP RS

2.4

Varity_R

0.30

gMVP

0.45

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