rs397516484

Positions:

• chr1-201359244-C-A
• chr1-201359244-C-G
• chr1-201359244-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 6P and 1B. PM1 PM2 PM5 BP4

The NM_001276345.2(TNNT2):​c.863G>T​(p.Arg288Leu) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R288C) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TNNT2 NM_001276345.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.79

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
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-201359245-G-A is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.39286822).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TNNT2	NM_001276345.2	c.863G>T	p.Arg288Leu	missense_variant	17/17	ENST00000656932.1	NP_001263274.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNNT2	ENST00000656932.1	c.863G>T	p.Arg288Leu	missense_variant	17/17		NM_001276345.2	ENSP00000499593	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
CardioboostCm	Uncertain	0.23
BayesDel_addAF	Uncertain	0.067	T
BayesDel_noAF	Benign	-0.14
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.67	.;.;.;.;D;.;.;.;.;.
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.96	.;D;D;D;D;D;D;.;.;D
M_CAP	Pathogenic	0.50	D
MetaRNN	Benign	0.39	T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.014	T
MutationAssessor	Benign	1.7	.;.;.;.;L;.;.;.;.;.
MutationTaster	Benign	0.93	D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-2.2	N;N;.;.;.;.;.;.;N;N
REVEL	Uncertain	0.45
Sift	Benign	0.12	T;T;.;.;.;.;.;.;D;T
Sift4G	Benign	0.14	T;T;T;T;T;T;T;T;T;T
Polyphen		0.97	.;.;.;.;D;.;.;.;.;.
Vest4		0.32
MutPred		0.40		.;.;.;.;Loss of methylation at R288 (P = 0.0188);.;.;.;.;.;
MVP		0.92
MPC		1.6
ClinPred		0.94	D
GERP RS		4.0
Varity_R		0.26
gMVP		0.58

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

LitVar

Other links and lift over

dbSNP: rs397516484; hg19: chr1-201328372;