rs727505027

chr1-201365273-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_001276345.2(TNNT2):c.329A>G(p.Asn110Ser) 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 1,461,878 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar 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, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.70

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 4 ACMG points.

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 12 uncertain in NM_001276345.2
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNNT2	NM_001276345.2	c.329A>G	p.Asn110Ser	missense_variant	10/17	ENST00000656932.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNNT2	ENST00000656932.1	c.329A>G	p.Asn110Ser	missense_variant	10/17		NM_001276345.2	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461878 Hom.: 0 Cov.: 33 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: 0.0000383

Gnomad4 EAS exome AF: 0.00

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:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 01, 2014

Variant classified as Uncertain Significance - Favor Pathogenic. The Asn100Ser v ariant in TNNT2 has not been previously reported in individuals with cardiomyopa thy or in large population studies. This variant was predicted to be pathogenic using a computational tool clinically validated by our laboratory. This tool's p athogenic prediction is estimated to be correct 94% of the time (Jordan 2011). I n addition, splicing prediction tools suggest this variant may lead to the creat ion of a novel splice site which could result in altered splicing, however this information is not predictive enough to determine pathogenicity. In summary, whi le these data suggest this variant may be disease-causing, additional informatio n is needed to fully assess the clinical significance of the Asn100Ser variant. -

Cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Dec 16, 2021

This missense variant replaces asparagine with serine at codon 100 of the TNNT2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
CardioboostCm	Benign	0.033
BayesDel_addAF	Uncertain	0.067	T
BayesDel_noAF	Benign	-0.14
Cadd	Uncertain	23
Dann	Benign	0.82
Eigen	Benign	-0.16
Eigen_PC	Benign	0.0032
FATHMM_MKL	Uncertain	0.81	D
M_CAP	Pathogenic	0.43	D
MetaRNN	Benign	0.39	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Pathogenic	0.86	D
MutationTaster	Benign	0.97	D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-0.26	N;N;.;.;.;.;.;N;N;N;N
REVEL	Benign	0.23
Sift	Benign	0.11	T;T;.;.;.;.;.;T;T;T;T
Sift4G	Benign	0.73	T;T;T;T;T;T;T;T;.;T;T
Polyphen		0.21, 0.79	.;.;.;B;.;.;.;.;P;.;.
Vest4		0.52
MutPred		0.29		.;.;.;Gain of phosphorylation at N110 (P = 0.0405);.;.;.;.;.;Gain of phosphorylation at N110 (P = 0.0405);.;
MVP		0.89
MPC		1.3
ClinPred		0.38	T
GERP RS		5.0
Varity_R		0.11
gMVP		0.59

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.30		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.30		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs727505027; hg19: chr1-201334401;