rs35559054

Positions:

• chr1-201364468-TG-T
• chr1-201364468-TG-TGG

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_001276345.2(TNNT2):​c.412-94del variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00946 in 1,303,710 control chromosomes in the GnomAD database, including 95 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0083 (9 hom., cov: 33)
  • Exomes 𝑓: 0.0096 (86 hom.)
• Consequence: TNNT2 NM_001276345.2 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.134

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 1-201364468-TG-T is Benign according to our data. Variant chr1-201364468-TG-T is described in ClinVar as [Likely_benign]. Clinvar id is 496075.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-201364468-TG-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00827 (1260/152336) while in subpopulation NFE AF= 0.012 (818/68024). AF 95% confidence interval is 0.0113. There are 9 homozygotes in gnomad4. There are 636 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1260 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TNNT2	NM_001276345.2	c.412-94del		intron_variant		ENST00000656932.1	NP_001263274.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNNT2	ENST00000656932.1	c.412-94del		intron_variant			NM_001276345.2	ENSP00000499593	A2

Frequencies

GnomAD3 genomes AF: 0.00828 AC: 1260 AN: 152218 Hom.: 9 Cov.: 33

Gnomad AFR AF: 0.00215

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00275

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0276

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0120

Gnomad OTH AF: 0.00239

GnomAD4 exome AF: 0.00962 AC: 11079 AN: 1151374 Hom.: 86 AF XY: 0.00925 AC XY: 5374 AN XY: 581196

Gnomad4 AFR exome AF: 0.00139

Gnomad4 AMR exome AF: 0.00199

Gnomad4 ASJ exome AF: 0.00401

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000132

Gnomad4 FIN exome AF: 0.0255

Gnomad4 NFE exome AF: 0.0112

Gnomad4 OTH exome AF: 0.00663

GnomAD4 genome AF: 0.00827 AC: 1260 AN: 152336 Hom.: 9 Cov.: 33 AF XY: 0.00854 AC XY: 636 AN XY: 74496

Gnomad4 AFR AF: 0.00214

Gnomad4 AMR AF: 0.00274

Gnomad4 ASJ AF: 0.00346

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0276

Gnomad4 NFE AF: 0.0120

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.0114 Hom.: 0

Bravo AF: 0.00661

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 19, 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	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 10, 2017	Variant summary: The TNNT2 c.382-94delC variant involves the alteration of a non-conserved intronic nucleotide. One in silico tool predicts a benign outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. This variant was found in 337/30938 control chromosomes at a frequency of 0.0108928, which is approximately 44 times the estimated maximal expected allele frequency of a pathogenic TNNT2 variant (0.00025), suggesting this variant is likely a benign polymorphism. This variant was reported in HCM patients without strong evidence for causality (Erdmann_CG_2003, Jaaskelainen_AM_2004). The variant of interest has not, to our knowledge, been reported by reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Due to the high frequency of this variant in the general population, the lack of impact on protein structure, and the lack of predicted impact on splicing, this variant has been classified as benign. -

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

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs35559054; hg19: chr1-201333596;