rs45509695

Positions:

• chr1-201359785-G-C

Variant summary

Our verdict is Benign. Variant got -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

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 -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 id is 671265.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-201359785-G-C is described in Lovd as [Benign].
• 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/exons	MANE	Protein	UniProt
TNNT2	NM_001276345.2	c.811-122C>G		intron_variant		ENST00000656932.1	NP_001263274.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNNT2	ENST00000656932.1	c.811-122C>G		intron_variant			NM_001276345.2	ENSP00000499593	A2

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

Gnomad4 AFR exome AF: 0.473

Gnomad4 AMR exome AF: 0.104

Gnomad4 ASJ exome AF: 0.131

Gnomad4 EAS exome AF: 0.231

Gnomad4 SAS exome AF: 0.202

Gnomad4 FIN exome AF: 0.137

Gnomad4 NFE exome AF: 0.0911

Gnomad4 OTH exome AF: 0.150

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

Gnomad4 AFR AF: 0.474

Gnomad4 AMR AF: 0.132

Gnomad4 ASJ AF: 0.130

Gnomad4 EAS AF: 0.260

Gnomad4 SAS AF: 0.217

Gnomad4 FIN AF: 0.123

Gnomad4 NFE AF: 0.0981

Gnomad4 OTH AF: 0.190

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

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 16, 2018	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, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jun 30, 2022	- -

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Dilated cardiomyopathy 1D Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Apr 11, 2023

- -

Cardiomyopathy, familial restrictive, 3 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Apr 11, 2023

- -

Hypertrophic cardiomyopathy 2 Benign:1

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

Jan 22, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.10
DANN	Benign	0.32

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: rs45509695; hg19: chr1-201328913; COSMIC: COSV52663053; COSMIC: COSV52663053;