rs1553281184

Positions:

• chr1-201363322-T-A

Variant summary

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

The NM_001276345.2(TNNT2):​c.574A>T​(p.Met192Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,888 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 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. M192I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TNNT2 NM_001276345.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.44

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM1: In a region_of_interest Disordered (size 99) in uniprot entity TNNT2_HUMAN there are 83 pathogenic changes around while only 5 benign (94%) in NM_001276345.2
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18084037).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNNT2	NM_001276345.2	c.574A>T	p.Met192Leu	missense_variant	12/17	ENST00000656932.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNNT2	ENST00000656932.1	c.574A>T	p.Met192Leu	missense_variant	12/17		NM_001276345.2	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461888 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727248

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 23, 2017

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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with TNNT2-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces methionine with leucine at codon 182 of the TNNT2 protein (p.Met182Leu). The methionine residue is weakly conserved and there is a small physicochemical difference between methionine and leucine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
CardioboostCm	Benign	0.053
BayesDel_addAF	Benign	-0.057	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	21
DANN	Benign	0.91
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.27
FATHMM_MKL	Benign	0.62	D
M_CAP	Benign	0.061	D
MetaRNN	Benign	0.18	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.95	T
MutationTaster	Benign	0.92	D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	0.16	N;N;.;.;.;.;.;.;N;N;N
REVEL	Benign	0.22
Sift	Benign	0.56	T;T;.;.;.;.;.;.;T;T;T
Sift4G	Benign	0.50	T;T;T;T;T;T;T;T;T;T;.
Polyphen		0.0010, 0.0020	.;.;.;.;B;.;.;.;.;.;B
Vest4		0.34
MutPred		0.40		.;.;.;.;Gain of catalytic residue at M192 (P = 0.0718);.;.;.;.;.;.;
MVP		0.76
MPC		0.47
ClinPred		0.80	D
GERP RS		3.7
Varity_R		0.16
gMVP		0.51

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

Other links and lift over

dbSNP: rs1553281184; hg19: chr1-201332450;