rs45533739

Positions:

• chr1-201372047-CAGAAG-C
• chr1-201372047-CAGAAG-CAGAAGAGAAG

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_001276345.2(TNNT2):​c.53-11_53-7del variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.603 in 1,612,828 control chromosomes in the GnomAD database, including 297,642 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.54 (23274 hom., cov: 0)
  • Exomes 𝑓: 0.61 (274368 hom.)
• Consequence: TNNT2 NM_001276345.2 splice_region, splice_polypyrimidine_tract, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:22
• Conservation: PhyloP100: 0.855

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP6: Variant 1-201372047-CAGAAG-C is Benign according to our data. Variant chr1-201372047-CAGAAG-C is described in ClinVar as [Likely_benign]. Clinvar id is 43652.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-201372047-CAGAAG-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.637 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNNT2	NM_001276345.2	c.53-11_53-7del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000656932.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNNT2	ENST00000656932.1	c.53-11_53-7del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			NM_001276345.2	A2

Frequencies

GnomAD3 genomes AF: 0.537 AC: 81149 AN: 151210 Hom.: 23259 Cov.: 0

Gnomad AFR AF: 0.310

Gnomad AMI AF: 0.496

Gnomad AMR AF: 0.647

Gnomad ASJ AF: 0.656

Gnomad EAS AF: 0.487

Gnomad SAS AF: 0.618

Gnomad FIN AF: 0.687

Gnomad MID AF: 0.503

Gnomad NFE AF: 0.619

Gnomad OTH AF: 0.554

GnomAD3 exomes AF: 0.602 AC: 151141 AN: 251208 Hom.: 46677 AF XY: 0.606 AC XY: 82320 AN XY: 135764

Gnomad AFR exome AF: 0.298

Gnomad AMR exome AF: 0.693

Gnomad ASJ exome AF: 0.645

Gnomad EAS exome AF: 0.480

Gnomad SAS exome AF: 0.626

Gnomad FIN exome AF: 0.668

Gnomad NFE exome AF: 0.613

Gnomad OTH exome AF: 0.621

GnomAD4 exome AF: 0.610 AC: 890790 AN: 1461500 Hom.: 274368 AF XY: 0.611 AC XY: 444518 AN XY: 727066

Gnomad4 AFR exome AF: 0.294

Gnomad4 AMR exome AF: 0.689

Gnomad4 ASJ exome AF: 0.653

Gnomad4 EAS exome AF: 0.508

Gnomad4 SAS exome AF: 0.624

Gnomad4 FIN exome AF: 0.664

Gnomad4 NFE exome AF: 0.615

Gnomad4 OTH exome AF: 0.602

GnomAD4 genome AF: 0.537 AC: 81189 AN: 151328 Hom.: 23274 Cov.: 0 AF XY: 0.541 AC XY: 39990 AN XY: 73888

Gnomad4 AFR AF: 0.310

Gnomad4 AMR AF: 0.647

Gnomad4 ASJ AF: 0.656

Gnomad4 EAS AF: 0.487

Gnomad4 SAS AF: 0.619

Gnomad4 FIN AF: 0.687

Gnomad4 NFE AF: 0.619

Gnomad4 OTH AF: 0.554

Alfa AF: 0.585 Hom.: 4882

Bravo AF: 0.523

Asia WGS AF: 0.527 AC: 1833 AN: 3478

EpiCase AF: 0.622

EpiControl AF: 0.616

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:22

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:8

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 07, 2006	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 25, 2013	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 12, 2015	- -

Cardiomyopathy Benign:3

Benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Apr 03, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 09, 2018	- -
Benign, no assertion criteria provided	clinical testing	Cohesion Phenomics	Oct 10, 2022	- -

Hypertrophic cardiomyopathy 2 Benign:3

Benign, no assertion criteria provided	clinical testing	Institute of Human Genetics, University of Wuerzburg	-	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 10, 2021	- -

Dilated cardiomyopathy 1D Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 10, 2021

- -

Dilated Cardiomyopathy, Dominant Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Nov 29, 2023

- -

Cardiomyopathy, familial restrictive, 3 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 10, 2021

- -

Left ventricular noncompaction cardiomyopathy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Hypertrophic 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

- -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs45533739; hg19: chr1-201341175;