rs869312881
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PP3_ModeratePP5
The NM_001276345.2(TNNT2):c.316G>A(p.Glu106Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: not found (cov: 32)
Consequence
TNNT2
NM_001276345.2 missense
NM_001276345.2 missense
Scores
12
3
2
Clinical Significance
Conservation
PhyloP100: 4.06
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
PM1
?
In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 12 uncertain in NM_001276345.2
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.875
PP5
?
Variant 1-201365286-C-T is Pathogenic according to our data. Variant chr1-201365286-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 224775.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1}. Variant chr1-201365286-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TNNT2 | NM_001276345.2 | c.316G>A | p.Glu106Lys | missense_variant | 10/17 | ENST00000656932.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TNNT2 | ENST00000656932.1 | c.316G>A | p.Glu106Lys | missense_variant | 10/17 | NM_001276345.2 | A2 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 33
GnomAD4 exome
Cov.:
33
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:2Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Dilated cardiomyopathy 1D Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jun 01, 2010 | - - |
Dilated cardiomyopathy 1D;C1861864:Hypertrophic cardiomyopathy 2;C2676271:Cardiomyopathy, familial restrictive, 3 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 09, 2024 | This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 96 of the TNNT2 protein (p.Glu96Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with dilated cardiomyopathy, dilated cardiomyopathy with left ventricular non-compaction and/or sudden cardiac death (PMID: 16715312, 20083571, 34076677; Invitae). It has also been observed to segregate with disease in related individuals. This variant is also known as p.E108K. ClinVar contains an entry for this variant (Variation ID: 224775). 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%. Experimental studies have shown that this missense change affects TNNT2 function (PMID: 20083571, 33025817). For these reasons, this variant has been classified as Pathogenic. - |
Cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Jan 20, 2020 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
CardioboostCm
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Pathogenic
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
D
MutationTaster
Benign
D;D;D;D;D;D;D;D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
D;D;.;D;N;.;N;D;D;D;D;D
REVEL
Pathogenic
Sift
Uncertain
D;D;.;D;D;.;T;D;D;D;D;D
Sift4G
Benign
T;T;T;T;T;T;T;T;.;T;D;.
Polyphen
1.0, 1.0
.;.;.;D;.;.;.;.;D;.;.;.
Vest4
MutPred
0.62
.;.;.;Gain of MoRF binding (P = 0.0049);.;.;.;.;.;Gain of MoRF binding (P = 0.0049);.;.;
MVP
MPC
1.5
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at