1-201365667-C-T

Variant names:

• chr1-201365667-C-T
• rs3729845
• NM_001276345.2:c.237G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001276345.2(TNNT2):​c.237G>A​(p.Ser79Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0663 in 1,613,624 control chromosomes in the GnomAD database, including 4,202 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. S79S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.087 (730 hom., cov: 32)
  • Exomes 𝑓: 0.064 (3472 hom.)
• Consequence: TNNT2 NM_001276345.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:20
• Conservation: PhyloP100: -3.67
• Publications: 15 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=-0.54).
• BP6: Variant 1-201365667-C-T is Benign according to our data. Variant chr1-201365667-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 43617.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.67 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.153 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.237G>A	p.Ser79Ser	synonymous	Exon 9 of 17	NP_001263274.1	P45379-1
	TNNT2	NM_000364.4		c.237G>A	p.Ser79Ser	synonymous	Exon 9 of 16	NP_000355.2
	TNNT2	NM_001406723.1		c.237G>A	p.Ser79Ser	synonymous	Exon 9 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.237G>A	p.Ser79Ser	synonymous	Exon 9 of 17	ENSP00000499593.1	P45379-1
	TNNT2	ENST00000367322.6	TSL:1	c.204G>A	p.Ser68Ser	synonymous	Exon 8 of 15	ENSP00000356291.2	A0A499FJM7
	TNNT2	ENST00000367320.6	TSL:1	c.234G>A	p.Ser78Ser	synonymous	Exon 9 of 15	ENSP00000356289.2	P45379-12

Frequencies

GnomAD3 genomes AF: 0.0870 AC: 13235 AN: 152088 Hom.: 730 Cov.: 32

Gnomad AFR AF: 0.156

Gnomad AMI AF: 0.0811

Gnomad AMR AF: 0.0582

Gnomad ASJ AF: 0.0571

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.0558

Gnomad FIN AF: 0.0662

Gnomad MID AF: 0.0791

Gnomad NFE AF: 0.0651

Gnomad OTH AF: 0.0917

GnomAD2 exomes AF: 0.0606 AC: 15184 AN: 250472 AF XY: 0.0600

Gnomad AFR exome AF: 0.155

Gnomad AMR exome AF: 0.0378

Gnomad ASJ exome AF: 0.0611

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.0673

Gnomad NFE exome AF: 0.0622

Gnomad OTH exome AF: 0.0557

GnomAD4 exome AF: 0.0642 AC: 93785 AN: 1461416 Hom.: 3472 Cov.: 31 AF XY: 0.0641 AC XY: 46576 AN XY: 726952

African (AFR) AF: 0.161 AC: 5399 AN: 33464

American (AMR) AF: 0.0387 AC: 1730 AN: 44684

Ashkenazi Jewish (ASJ) AF: 0.0600 AC: 1567 AN: 26122

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.0636 AC: 5478 AN: 86114

European-Finnish (FIN) AF: 0.0616 AC: 3290 AN: 53404

Middle Eastern (MID) AF: 0.0862 AC: 497 AN: 5768

European-Non Finnish (NFE) AF: 0.0647 AC: 71895 AN: 1111774

Other (OTH) AF: 0.0650 AC: 3928 AN: 60386

GnomAD4 genome AF: 0.0870 AC: 13236 AN: 152208 Hom.: 730 Cov.: 32 AF XY: 0.0852 AC XY: 6338 AN XY: 74418

African (AFR) AF: 0.156 AC: 6465 AN: 41506

American (AMR) AF: 0.0581 AC: 889 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0571 AC: 198 AN: 3470

East Asian (EAS) AF: 0.000578 AC: 3 AN: 5188

South Asian (SAS) AF: 0.0558 AC: 269 AN: 4818

European-Finnish (FIN) AF: 0.0662 AC: 702 AN: 10600

Middle Eastern (MID) AF: 0.0714 AC: 21 AN: 294

European-Non Finnish (NFE) AF: 0.0651 AC: 4425 AN: 68024

Other (OTH) AF: 0.0903 AC: 190 AN: 2104

Alfa AF: 0.0675 Hom.: 776

Bravo AF: 0.0892

Asia WGS AF: 0.0300 AC: 107 AN: 3478

EpiCase AF: 0.0674

EpiControl AF: 0.0704

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	2	Hypertrophic cardiomyopathy (2)
-	-	2	not provided (2)
-	-	1	Cardiomyopathy (1)
-	-	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	-0.54
CADD	Benign	1.6
DANN	Benign	0.76
PhyloP100		-3.7
Mutation Taster		=100/0	polymorphism (auto)

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: rs3729845; hg19: chr1-201334795;