rs3729547

Variant names:

• chr1-201365254-G-A
• rs3729547
• NM_001276345.2:c.348C>T

Your query was ambiguous. Multiple possible variants found:

• chr1-201365254-G-A
• chr1-201365254-G-C

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001276345.2(TNNT2):​c.348C>T​(p.Ile116Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.714 in 1,613,718 control chromosomes in the GnomAD database, including 413,386 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). The gene TNNT2 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.70 (37423 hom., cov: 31)
  • Exomes 𝑓: 0.72 (375963 hom.)
• Consequence: TNNT2 NM_001276345.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:23
• Conservation: PhyloP100: 0.348
• Publications: 43 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

Specifications for TNNT2 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.32).
• BP6: Variant 1-201365254-G-A is Benign according to our data. Variant chr1-201365254-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 43632.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.348 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.793 is higher than 0.05.

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.348C>T	p.Ile116Ile	synonymous	Exon 10 of 17	NP_001263274.1	P45379-1
	TNNT2	NM_000364.4		c.348C>T	p.Ile116Ile	synonymous	Exon 10 of 16	NP_000355.2
	TNNT2	NM_001406723.1		c.348C>T	p.Ile116Ile	synonymous	Exon 10 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.348C>T	p.Ile116Ile	synonymous	Exon 10 of 17	ENSP00000499593.1	P45379-1
	TNNT2	ENST00000367322.6	TSL:1	c.315C>T	p.Ile105Ile	synonymous	Exon 9 of 15	ENSP00000356291.2	A0A499FJM7
	TNNT2	ENST00000367320.6	TSL:1	c.291+356C>T		intron	N/A	ENSP00000356289.2	P45379-12

Frequencies

GnomAD3 genomes AF: 0.699 AC: 106151 AN: 151904 Hom.: 37406 Cov.: 31

Gnomad AFR AF: 0.622

Gnomad AMI AF: 0.605

Gnomad AMR AF: 0.754

Gnomad ASJ AF: 0.782

Gnomad EAS AF: 0.553

Gnomad SAS AF: 0.815

Gnomad FIN AF: 0.802

Gnomad MID AF: 0.753

Gnomad NFE AF: 0.716

Gnomad OTH AF: 0.706

GnomAD2 exomes AF: 0.723 AC: 181760 AN: 251482 AF XY: 0.729

Gnomad AFR exome AF: 0.618

Gnomad AMR exome AF: 0.766

Gnomad ASJ exome AF: 0.772

Gnomad EAS exome AF: 0.544

Gnomad FIN exome AF: 0.790

Gnomad NFE exome AF: 0.710

Gnomad OTH exome AF: 0.749

GnomAD4 exome AF: 0.716 AC: 1046009 AN: 1461696 Hom.: 375963 Cov.: 60 AF XY: 0.720 AC XY: 523486 AN XY: 727164

African (AFR) AF: 0.619 AC: 20718 AN: 33478

American (AMR) AF: 0.765 AC: 34225 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.777 AC: 20318 AN: 26136

East Asian (EAS) AF: 0.575 AC: 22836 AN: 39700

South Asian (SAS) AF: 0.813 AC: 70115 AN: 86258

European-Finnish (FIN) AF: 0.791 AC: 42234 AN: 53416

Middle Eastern (MID) AF: 0.746 AC: 4302 AN: 5768

European-Non Finnish (NFE) AF: 0.708 AC: 787542 AN: 1111824

Other (OTH) AF: 0.724 AC: 43719 AN: 60392

GnomAD4 genome AF: 0.699 AC: 106218 AN: 152022 Hom.: 37423 Cov.: 31 AF XY: 0.705 AC XY: 52359 AN XY: 74302

African (AFR) AF: 0.622 AC: 25777 AN: 41432

American (AMR) AF: 0.754 AC: 11524 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.782 AC: 2714 AN: 3472

East Asian (EAS) AF: 0.554 AC: 2859 AN: 5162

South Asian (SAS) AF: 0.814 AC: 3916 AN: 4812

European-Finnish (FIN) AF: 0.802 AC: 8480 AN: 10578

Middle Eastern (MID) AF: 0.755 AC: 222 AN: 294

European-Non Finnish (NFE) AF: 0.716 AC: 48680 AN: 67960

Other (OTH) AF: 0.706 AC: 1494 AN: 2116

Alfa AF: 0.708 Hom.: 180921

Bravo AF: 0.686

Asia WGS AF: 0.676 AC: 2353 AN: 3478

EpiCase AF: 0.715

EpiControl AF: 0.718

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	9	not specified (9)
-	-	2	Cardiomyopathy (2)
-	-	2	Hypertrophic cardiomyopathy (2)
-	-	2	not provided (2)
-	-	1	Cardiomyopathy, familial restrictive, 3 (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Dilated cardiomyopathy 1D (1)
-	-	1	Dilated cardiomyopathy 1D;C1861864:Hypertrophic cardiomyopathy 2;C2676271:Cardiomyopathy, familial restrictive, 3 (1)
-	-	1	Dilated Cardiomyopathy, Dominant (1)
-	-	1	Familial restrictive cardiomyopathy (1)
-	-	1	Hypertrophic cardiomyopathy 2 (1)
-	-	1	Left ventricular noncompaction cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.32
CADD	Benign	7.2
DANN	Benign	0.82
PhyloP100		0.35
Mutation Taster		=89/11	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3729547; hg19: chr1-201334382; COSMIC: COSV52661393; COSMIC: COSV52661393;