NM_001276345.2:c.474G>C

Variant names:

• chr1-201364313-C-G
• rs35914325
• NM_001276345.2:c.474G>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001276345.2(TNNT2):​c.474G>C​(p.Arg158Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00145 in 1,612,856 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. R158R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0072 (4 hom., cov: 33)
  • Exomes 𝑓: 0.00085 (12 hom.)
• Consequence: TNNT2 NM_001276345.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:19
• Conservation: PhyloP100: -3.04
• Publications: 2 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant 1-201364313-C-G is Benign according to our data. Variant chr1-201364313-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 43641.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.04 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00721 (1098/152346) while in subpopulation AFR AF = 0.0249 (1037/41584). AF 95% confidence interval is 0.0237. There are 4 homozygotes in GnomAd4. There are 513 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AD,AR gene

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.474G>C	p.Arg158Arg	synonymous	Exon 11 of 17	NP_001263274.1	P45379-1
	TNNT2	NM_000364.4		c.474G>C	p.Arg158Arg	synonymous	Exon 11 of 16	NP_000355.2
	TNNT2	NM_001406723.1		c.474G>C	p.Arg158Arg	synonymous	Exon 11 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.474G>C	p.Arg158Arg	synonymous	Exon 11 of 17	ENSP00000499593.1	P45379-1
	TNNT2	ENST00000367322.6	TSL:1	c.441G>C	p.Arg147Arg	synonymous	Exon 10 of 15	ENSP00000356291.2	A0A499FJM7
	TNNT2	ENST00000367320.6	TSL:1	c.354G>C	p.Arg118Arg	synonymous	Exon 10 of 15	ENSP00000356289.2	P45379-12

Frequencies

GnomAD3 genomes AF: 0.00720 AC: 1096 AN: 152228 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.0250

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00268

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00334

GnomAD2 exomes AF: 0.00200 AC: 498 AN: 249194 AF XY: 0.00139

Gnomad AFR exome AF: 0.0262

Gnomad AMR exome AF: 0.00177

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000796

Gnomad OTH exome AF: 0.000492

GnomAD4 exome AF: 0.000853 AC: 1246 AN: 1460510 Hom.: 12 Cov.: 31 AF XY: 0.000738 AC XY: 536 AN XY: 726562

African (AFR) AF: 0.0257 AC: 859 AN: 33474

American (AMR) AF: 0.00183 AC: 82 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.000128 AC: 11 AN: 86098

European-Finnish (FIN) AF: 0.0000191 AC: 1 AN: 52400

Middle Eastern (MID) AF: 0.00174 AC: 10 AN: 5756

European-Non Finnish (NFE) AF: 0.000161 AC: 179 AN: 1111910

Other (OTH) AF: 0.00172 AC: 104 AN: 60342

GnomAD4 genome AF: 0.00721 AC: 1098 AN: 152346 Hom.: 4 Cov.: 33 AF XY: 0.00689 AC XY: 513 AN XY: 74492

African (AFR) AF: 0.0249 AC: 1037 AN: 41584

American (AMR) AF: 0.00268 AC: 41 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000162 AC: 11 AN: 68030

Other (OTH) AF: 0.00331 AC: 7 AN: 2116

Alfa AF: 0.00263 Hom.: 2

Bravo AF: 0.00839

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	not provided (3)
-	-	2	Cardiomyopathy (2)
-	-	2	Cardiomyopathy, familial restrictive, 3 (2)
-	-	2	Hypertrophic cardiomyopathy 2 (2)
-	-	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	Hypertrophic cardiomyopathy (1)
-	-	1	Left ventricular noncompaction cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	8.2
DANN	Benign	0.78
PhyloP100		-3.0
Mutation Taster		=99/1	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: rs35914325; hg19: chr1-201333441;