1-201366863-T-G

Position:

• chr1-201366863-T-G

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.208A>C​(p.Met70Leu) 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. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TNNT2 NM_001276345.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.627

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 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
• BP4: Computational evidence support a benign effect (MetaRNN=0.16692227).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TNNT2	NM_001276345.2	c.208A>C	p.Met70Leu	missense_variant	8/17	ENST00000656932.1	NP_001263274.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNNT2	ENST00000656932.1	c.208A>C	p.Met70Leu	missense_variant	8/17		NM_001276345.2	ENSP00000499593	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 25, 2015

proposed classification - variant undergoing re-assessment, contact laboratory -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
CardioboostCm	Benign	0.027
BayesDel_addAF	Uncertain	0.044	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	10
DANN	Benign	0.71
DEOGEN2	Benign	0.35	.;.;.;.;T;.;.;.;.;.;T;.;.;T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.93
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.69	.;T;T;T;T;D;T;.;.;T;.;.;T;.
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.072	T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.28	D
MutationAssessor	Benign	0.0	.;.;.;.;N;.;.;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.48	N;N;.;.;.;N;.;N;N;N;N;N;N;N
REVEL	Uncertain	0.34
Sift	Benign	0.49	T;T;.;.;.;D;.;D;T;T;T;T;T;D
Sift4G	Benign	0.66	T;T;T;T;T;T;T;T;T;T;.;T;T;.
Polyphen		0.0	.;.;.;.;B;.;.;.;.;.;B;.;.;.
Vest4		0.20
MutPred		0.18		.;.;.;.;Gain of stability (P = 0.1659);.;.;.;.;.;.;Gain of stability (P = 0.1659);.;.;
MVP		0.68
MPC		0.47
ClinPred		0.029	T
GERP RS		2.8
Varity_R		0.18
gMVP		0.25

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: rs141837529; hg19: chr1-201335991;