1-201362015-C-T
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 4P and 5B. PM1PM5BP4BS2
The NM_001276345.2(TNNT2):c.617G>A(p.Arg206Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000123 in 1,461,882 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R206W) has been classified as Likely pathogenic.
Frequency
Consequence
NM_001276345.2 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Likely_benign. Variant got -1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TNNT2 | NM_001276345.2 | c.617G>A | p.Arg206Gln | missense_variant | 14/17 | ENST00000656932.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TNNT2 | ENST00000656932.1 | c.617G>A | p.Arg206Gln | missense_variant | 14/17 | NM_001276345.2 | A2 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 exomes AF: 0.00000795 AC: 2AN: 251486Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135920
GnomAD4 exome AF: 0.0000123 AC: 18AN: 1461882Hom.: 0 Cov.: 32 AF XY: 0.0000124 AC XY: 9AN XY: 727248
GnomAD4 genome Cov.: 33
ClinVar
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 | Fulgent Genetics, Fulgent Genetics | Jul 28, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jun 17, 2023 | 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on TNNT2 protein function. 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. ClinVar contains an entry for this variant (Variation ID: 537255). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 31514951). This variant is present in population databases (rs371047521, gnomAD 0.006%). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 196 of the TNNT2 protein (p.Arg196Gln). - |
Dilated cardiomyopathy 1D Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Apr 11, 2023 | - - |
Cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jun 20, 2023 | This missense variant replaces arginine with glutamine at codon 196 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individuals affected with dilated cardiomyopathy (PMID: 31514951, 34935411). One of these individuals also carried a pathogenic truncation variant in the TTN gene (PMID: 34935411). This variant has been identified in 3/282874 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. - |
See cases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University Hospital Muenster | Oct 20, 2023 | ACMG categories: PM5 - |
Cardiomyopathy, familial restrictive, 3 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Apr 11, 2023 | - - |
Hypertrophic cardiomyopathy 2 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 | Nov 10, 2023 | The p.R196Q variant (also known as c.587G>A), located in coding exon 12 of the TNNT2 gene, results from a G to A substitution at nucleotide position 587. The arginine at codon 196 is replaced by glutamine, an amino acid with highly similar properties. This variant has been detected in a dilated cardiomyopathy (DCM) cohort; however, details were limited (Gigli M et al. J Am Coll Cardiol. 2019 09;74(11):1480-1490). This amino acid position is not 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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at