NM_001276345.2:c.682G>C

Variant names:

• chr1-201361950-C-G
• rs397516479
• NM_001276345.2:c.682G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001276345.2(TNNT2):​c.682G>C​(p.Val228Leu) 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 1,461,892 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 (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • 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: 2.34
• Publications: 3 publications found

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]

TNNT2 Gene-Disease associations (from GenCC):

• dilated cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• dilated cardiomyopathy 1D

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• hypertrophic cardiomyopathy 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• hypertrophic cardiomyopathy 3

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• cardiomyopathy, familial restrictive, 3

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• hypertrophic cardiomyopathy

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial isolated restrictive cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• left ventricular noncompaction

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• cardiomyopathy

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics
• arrhythmogenic right ventricular cardiomyopathy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ENSG00000286600 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.4229712).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001276345.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNNT2	NM_001276345.2	MANE Select	c.682G>C	p.Val228Leu	missense	Exon 14 of 17	NP_001263274.1	P45379-1
	TNNT2	NM_000364.4		c.673G>C	p.Val225Leu	missense	Exon 13 of 16	NP_000355.2
	TNNT2	NM_001406723.1		c.673G>C	p.Val225Leu	missense	Exon 13 of 16	NP_001393652.1	P45379-10

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNNT2	ENST00000656932.1	MANE Select	c.682G>C	p.Val228Leu	missense	Exon 14 of 17	ENSP00000499593.1	P45379-1
	TNNT2	ENST00000367322.6	TSL:1	c.640G>C	p.Val214Leu	missense	Exon 12 of 15	ENSP00000356291.2	A0A499FJM7
	TNNT2	ENST00000367320.6	TSL:1	c.553G>C	p.Val185Leu	missense	Exon 12 of 15	ENSP00000356289.2	P45379-12

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251490 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461892 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727246

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112010

Other (OTH) AF: 0.0000166 AC: 1 AN: 60396

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Cardiomyopathy (1)
-	1	-	Dilated cardiomyopathy 1D;C1861864:Hypertrophic cardiomyopathy 2;C2676271:Cardiomyopathy, familial restrictive, 3 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
CardioboostCm	Benign	0.074
BayesDel_addAF	Benign	-0.025	T
BayesDel_noAF	Benign	-0.18
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.60	D
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.076
FATHMM_MKL	Benign	0.16	N
LIST_S2	Uncertain	0.88	D
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.42	T
MetaSVM	Benign	-0.63	T
MutationAssessor	Benign	0.69	N
PhyloP100		2.3
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-1.0	N
REVEL	Uncertain	0.37
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0090	D
Polyphen		0.075	B
Vest4		0.34
MutPred		0.56		Loss of methylation at K227 (P = 0.0342)
MVP		0.82
MPC		0.55
ClinPred		0.36	T
GERP RS		3.5
Varity_R		0.29
gMVP		0.73
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

dbSNP: rs397516479; hg19: chr1-201331078;