rs193922620

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001276345.2(TNNT2):​c.851+5G>C variant causes a splice region, intron change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

TNNT2
NM_001276345.2 splice_region, intron

Scores

2
Splicing: ADA: 1.000
2

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 6.83
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TNNT2NM_001276345.2 linkc.851+5G>C splice_region_variant, intron_variant Intron 16 of 16 ENST00000656932.1 NP_001263274.1 P45379-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TNNT2ENST00000656932.1 linkc.851+5G>C splice_region_variant, intron_variant Intron 16 of 16 NM_001276345.2 ENSP00000499593.1 P45379-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
0.00
AC:
0
AN:
1447102
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
718260
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Dilated cardiomyopathy 1D Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingPhosphorus, Inc.Aug 01, 2017- -
Cardiomyopathy, familial restrictive, 3 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingPhosphorus, Inc.Aug 01, 2017- -
Hypertrophic cardiomyopathy 2 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingPhosphorus, Inc.Aug 01, 2017- -
Dilated cardiomyopathy 1D;C1861864:Hypertrophic cardiomyopathy 2;C2676271:Cardiomyopathy, familial restrictive, 3 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpAug 31, 2024This sequence change falls in intron 15 of the TNNT2 gene. It does not directly change the encoded amino acid sequence of the TNNT2 protein. It affects a nucleotide within the consensus splice site. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with TNNT2-related conditions. ClinVar contains an entry for this variant (Variation ID: 488163). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.17
CADD
Benign
21
DANN
Benign
0.95

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.99
SpliceAI score (max)
0.72
Details are displayed if max score is > 0.2
DS_DG_spliceai
0.48
Position offset: -8
DS_DL_spliceai
0.72
Position offset: 5

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs193922620; hg19: chr1-201328746; API