1-201365667-C-T

Position:

• chr1-201365667-C-T

Variant summary

Our verdict is Benign. Variant got -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

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id is 43617.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-201365667-C-T is described in Lovd as [Benign].
• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TNNT2	NM_001276345.2	c.237G>A	p.Ser79Ser	synonymous_variant	9/17	ENST00000656932.1	NP_001263274.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNNT2	ENST00000656932.1	c.237G>A	p.Ser79Ser	synonymous_variant	9/17		NM_001276345.2	ENSP00000499593.1

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

GnomAD3 exomes AF: 0.0606 AC: 15184 AN: 250472 Hom.: 607 AF XY: 0.0600 AC XY: 8124 AN XY: 135340

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 SAS exome AF: 0.0636

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

Gnomad4 AFR exome AF: 0.161

Gnomad4 AMR exome AF: 0.0387

Gnomad4 ASJ exome AF: 0.0600

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0636

Gnomad4 FIN exome AF: 0.0616

Gnomad4 NFE exome AF: 0.0647

Gnomad4 OTH exome AF: 0.0650

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

Gnomad4 AFR AF: 0.156

Gnomad4 AMR AF: 0.0581

Gnomad4 ASJ AF: 0.0571

Gnomad4 EAS AF: 0.000578

Gnomad4 SAS AF: 0.0558

Gnomad4 FIN AF: 0.0662

Gnomad4 NFE AF: 0.0651

Gnomad4 OTH AF: 0.0903

Alfa AF: 0.0651 Hom.: 514

Bravo AF: 0.0892

Asia WGS AF: 0.0300 AC: 107 AN: 3478

EpiCase AF: 0.0674

EpiControl AF: 0.0704

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:20

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 29, 2017	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	Sep 24, 2019	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Hypertrophic cardiomyopathy Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Benign, no assertion criteria provided	clinical testing	Cohesion Phenomics	Sep 27, 2022	- -

Dilated cardiomyopathy 1D Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Apr 11, 2023

- -

Cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Mar 15, 2018

- -

Dilated Cardiomyopathy, Dominant Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Cardiomyopathy, familial restrictive, 3 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Apr 11, 2023

- -

Left ventricular noncompaction cardiomyopathy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Familial restrictive cardiomyopathy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 15, 2015

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Hypertrophic cardiomyopathy 2 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Apr 11, 2023

- -

Dilated cardiomyopathy 1D;C1861864:Hypertrophic cardiomyopathy 2;C2676271:Cardiomyopathy, familial restrictive, 3 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	1.6
DANN	Benign	0.76

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

Publications

LitVar

Other links and lift over

dbSNP: rs3729845; hg19: chr1-201334795;