NM_001276345.2:c.811-122C>G

Variant names:

• chr1-201359785-G-C
• rs45509695
• NM_001276345.2:c.811-122C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001276345.2(TNNT2):​c.811-122C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.142 in 856,660 control chromosomes in the GnomAD database, including 13,285 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.22 (5529 hom., cov: 32)
  • Exomes 𝑓: 0.13 (7756 hom.)
• Consequence: TNNT2 NM_001276345.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -2.28
• Publications: 6 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: Labcorp Genetics (formerly Invitae), Ambry Genetics
• hypertrophic cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• hypertrophic cardiomyopathy 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• hypertrophic cardiomyopathy 3

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• cardiomyopathy, familial restrictive, 3

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BP6: Variant 1-201359785-G-C is Benign according to our data. Variant chr1-201359785-G-C is described in ClinVar as Benign. ClinVar VariationId is 671265.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.468 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNNT2	NM_001276345.2	c.811-122C>G		intron_variant	Intron 15 of 16	ENST00000656932.1	NP_001263274.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNNT2	ENST00000656932.1	c.811-122C>G		intron_variant	Intron 15 of 16		NM_001276345.2	ENSP00000499593.1

Frequencies

GnomAD3 genomes AF: 0.217 AC: 32940 AN: 151960 Hom.: 5502 Cov.: 32

Gnomad AFR AF: 0.473

Gnomad AMI AF: 0.105

Gnomad AMR AF: 0.132

Gnomad ASJ AF: 0.130

Gnomad EAS AF: 0.260

Gnomad SAS AF: 0.218

Gnomad FIN AF: 0.123

Gnomad MID AF: 0.250

Gnomad NFE AF: 0.0980

Gnomad OTH AF: 0.192

GnomAD4 exome AF: 0.126 AC: 88658 AN: 704582 Hom.: 7756 AF XY: 0.128 AC XY: 47708 AN XY: 372534

African (AFR) AF: 0.473 AC: 8391 AN: 17724

American (AMR) AF: 0.104 AC: 3610 AN: 34840

Ashkenazi Jewish (ASJ) AF: 0.131 AC: 2737 AN: 20866

East Asian (EAS) AF: 0.231 AC: 7517 AN: 32606

South Asian (SAS) AF: 0.202 AC: 13060 AN: 64804

European-Finnish (FIN) AF: 0.137 AC: 6681 AN: 48672

Middle Eastern (MID) AF: 0.191 AC: 818 AN: 4282

European-Non Finnish (NFE) AF: 0.0911 AC: 40593 AN: 445692

Other (OTH) AF: 0.150 AC: 5251 AN: 35096

GnomAD4 genome AF: 0.217 AC: 33012 AN: 152078 Hom.: 5529 Cov.: 32 AF XY: 0.218 AC XY: 16231 AN XY: 74350

African (AFR) AF: 0.474 AC: 19606 AN: 41406

American (AMR) AF: 0.132 AC: 2021 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.130 AC: 452 AN: 3472

East Asian (EAS) AF: 0.260 AC: 1346 AN: 5170

South Asian (SAS) AF: 0.217 AC: 1046 AN: 4826

European-Finnish (FIN) AF: 0.123 AC: 1302 AN: 10600

Middle Eastern (MID) AF: 0.252 AC: 74 AN: 294

European-Non Finnish (NFE) AF: 0.0981 AC: 6667 AN: 67994

Other (OTH) AF: 0.190 AC: 402 AN: 2112

Alfa AF: 0.168 Hom.: 446

Bravo AF: 0.229

Asia WGS AF: 0.263 AC: 915 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 30, 2022

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 16, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not specified Benign:2

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dilated cardiomyopathy 1D Benign:1

Apr 11, 2023

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiomyopathy, familial restrictive, 3 Benign:1

Apr 11, 2023

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hypertrophic cardiomyopathy 2 Benign:1

Apr 11, 2023

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.10
DANN	Benign	0.32
PhyloP100		-2.3
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: rs45509695; hg19: chr1-201328913; COSMIC: COSV52663053; COSMIC: COSV52663053;