1-201365254-G-C

Position:

• chr1-201365254-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP3

The NM_001276345.2(TNNT2):​c.348C>G​(p.Ile116Met) 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 pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. I116I) has been classified as Benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: TNNT2 NM_001276345.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.348

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
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.824

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TNNT2	NM_001276345.2	c.348C>G	p.Ile116Met	missense_variant	10/17	ENST00000656932.1	NP_001263274.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNNT2	ENST00000656932.1	c.348C>G	p.Ile116Met	missense_variant	10/17		NM_001276345.2	ENSP00000499593	A2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 60

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
CardioboostCm	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.95	.;.;.;D;.;.;.;.;D;.;.
Eigen	Benign	0.11
Eigen_PC	Benign	0.0044
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Pathogenic	1.0	.;D;D;D;D;D;.;D;.;.;D
M_CAP	Pathogenic	0.79	D
MetaRNN	Pathogenic	0.82	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.1	.;.;.;M;.;.;.;.;.;.;.
MutationTaster	Benign	2.8e-7	P;P;P;P;P;P;P;P;P;P
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-2.9	D;D;.;.;.;.;.;D;D;D;D
REVEL	Pathogenic	0.76
Sift	Pathogenic	0.0	D;D;.;.;.;.;.;D;D;D;D
Sift4G	Uncertain	0.0060	D;D;D;D;D;D;D;D;.;D;T
Polyphen		1.0	.;.;.;D;.;.;.;.;D;.;.
Vest4		0.86
MutPred		0.37		.;.;.;Loss of stability (P = 0.3128);.;.;.;.;.;Loss of stability (P = 0.3128);.;
MVP		0.93
MPC		1.4
ClinPred		0.99	D
GERP RS		3.1
Varity_R		0.69
gMVP		0.94

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: rs3729547; hg19: chr1-201334382;