1-201359632-T-C

Position:

• chr1-201359632-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 6P and 2B. PM1 PM2 PM5 BP4_Moderate

The NM_001276345.2(TNNT2):​c.842A>G​(p.Asn281Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict 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. N281I) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TNNT2 NM_001276345.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.93

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a hotspot region, there are 3 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
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-201359632-T-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 217495.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=4, Likely_pathogenic=6}.
• BP4: Computational evidence support a benign effect (MetaRNN=0.24187735).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TNNT2	NM_001276345.2	c.842A>G	p.Asn281Ser	missense_variant	16/17	ENST00000656932.1	NP_001263274.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNNT2	ENST00000656932.1	c.842A>G	p.Asn281Ser	missense_variant	16/17		NM_001276345.2	ENSP00000499593.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Dec 21, 2023

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 03, 2024

This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 271 of the TNNT2 protein (p.Asn271Ser). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with TNNT2-related conditions. ClinVar contains an entry for this variant (Variation ID: 1406501). 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. This variant disrupts the p.Asn271 amino acid residue in TNNT2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12707239, 20038417, 22857948, 23396983; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
CardioboostCm	Benign	0.046
BayesDel_addAF	Benign	-0.099	T
BayesDel_noAF	Benign	-0.38
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.51	.;.;.;.;D;.;.;.;.;.;T
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.0066
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.94	.;D;D;D;D;D;D;.;.;D;.
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.24	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.50	T
MutationAssessor	Benign	0.34	.;.;.;.;N;.;.;.;.;.;.
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-0.38	N;N;.;.;.;.;.;.;N;N;N
REVEL	Benign	0.24
Sift	Benign	0.59	T;T;.;.;.;.;.;.;T;T;T
Sift4G	Benign	0.47	T;T;T;T;T;T;T;T;T;T;.
Polyphen		0.46	.;.;.;.;P;.;.;.;.;.;.
Vest4		0.41
MutPred		0.24		.;.;.;.;Loss of methylation at K283 (P = 0.131);.;.;.;.;.;.;
MVP		0.86
MPC		0.72
ClinPred		0.45	T
GERP RS		4.1
Varity_R		0.63
gMVP		0.53

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-201328760;