rs727504488

Positions:

• chr1-201361305-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP5

The NM_001276345.2(TNNT2):​c.784G>A​(p.Glu262Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: TNNT2 NM_001276345.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 2.98

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 5 ACMG points.

• PM1: In a chain Troponin T, cardiac muscle (size 296) in uniprot entity TNNT2_HUMAN there are 88 pathogenic changes around while only 9 benign (91%) in NM_001276345.2
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-201361305-C-T is Pathogenic according to our data. Variant chr1-201361305-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 178850.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TNNT2	NM_001276345.2	c.784G>A	p.Glu262Lys	missense_variant	15/17	ENST00000656932.1	NP_001263274.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNNT2	ENST00000656932.1	c.784G>A	p.Glu262Lys	missense_variant	15/17		NM_001276345.2	ENSP00000499593	A2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Primary familial dilated cardiomyopathy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Apr 28, 2017

- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Sep 24, 2013

The Glu252Lys variant in TNNT2 has now been identified by our laboratory in 2 Ca ucasian individuals with DCM and segregated with disease in 1 affected relative. It has not been identified in large population studies. Computational analyses (biochemical amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT ) suggest that the Glu252Lys variant may not impact the protein, though this inf ormation is not predictive enough to rule out pathogenicity. Additional informat ion is needed to fully assess the clinical significance of this variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.76
CardioboostCm	Benign	0.041
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.030
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.83	.;.;.;.;D;.;.;.;.;.;D
Eigen	Benign	-0.020
Eigen_PC	Benign	0.063
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.95	.;D;D;D;D;D;D;.;.;D;.
M_CAP	Pathogenic	0.43	D
MetaRNN	Uncertain	0.62	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.17	D
MutationAssessor	Benign	1.8	.;.;.;.;L;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-2.4	N;N;D;.;.;.;.;.;D;N;N
REVEL	Uncertain	0.63
Sift	Uncertain	0.021	D;D;D;.;.;.;.;.;D;D;D
Sift4G	Uncertain	0.035	D;D;D;T;D;T;D;T;T;D;.
Polyphen		0.073	.;.;.;.;B;.;.;.;.;.;.
Vest4		0.51
MutPred		0.41		.;.;.;.;Gain of MoRF binding (P = 0.0081);.;.;.;.;.;.;
MVP		0.90
MPC		0.91
ClinPred		0.88	D
GERP RS		3.7
Varity_R		0.58
gMVP		0.74

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: rs727504488; hg19: chr1-201330433;