3-52451412-CGTT-C
Position:
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PM2PM4_Supporting
The NM_003280.3(TNNC1):βc.430_432delβ(p.Asn144del) variant causes a inframe deletion change. The variant allele was found at a frequency of 0.00000274 in 1,461,858 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (β β ). Synonymous variant affecting the same amino acid position (i.e. N144N) has been classified as Likely benign.
Frequency
Genomes: not found (cov: 32)
Exomes π: 0.0000027 ( 0 hom. )
Consequence
TNNC1
NM_003280.3 inframe_deletion
NM_003280.3 inframe_deletion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 5.03
Genes affected
TNNC1 (HGNC:11943): (troponin C1, slow skeletal and cardiac type) Troponin is a central regulatory protein of striated muscle contraction, and together with tropomyosin, is located on the actin filament. Troponin consists of 3 subunits: TnI, which is the inhibitor of actomyosin ATPase; TnT, which contains the binding site for tropomyosin; and TnC, the protein encoded by this gene. The binding of calcium to TnC abolishes the inhibitory action of TnI, thus allowing the interaction of actin with myosin, the hydrolysis of ATP, and the generation of tension. Mutations in this gene are associated with cardiomyopathy dilated type 1Z. [provided by RefSeq, Oct 2008]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 5 ACMG points.
PM1
In a chain Troponin C, slow skeletal and cardiac muscles (size 160) in uniprot entity TNNC1_HUMAN there are 27 pathogenic changes around while only 0 benign (100%) in NM_003280.3
PM2
Very rare variant in population databases, with high coverage;
PM4
Nonframeshift variant in NON repetitive region in NM_003280.3. Strenght limited to Supporting due to length of the change: 1aa.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TNNC1 | NM_003280.3 | c.430_432del | p.Asn144del | inframe_deletion | 5/6 | ENST00000232975.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TNNC1 | ENST00000232975.8 | c.430_432del | p.Asn144del | inframe_deletion | 5/6 | 1 | NM_003280.3 | P1 | |
TNNC1 | ENST00000496590.1 | incomplete_terminal_codon_variant, coding_sequence_variant, 3_prime_UTR_variant | 4/4 | 2 | |||||
TNNC1 | ENST00000461086.1 | downstream_gene_variant | 2 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461858Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 727228
GnomAD4 exome
AF:
AC:
4
AN:
1461858
Hom.:
AF XY:
AC XY:
0
AN XY:
727228
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jan 30, 2018 | A variant of uncertain significance has been identified in the TNNC1 gene. The c.430_432delAAC variant has not been published as pathogenic or been reported as benign to our knowledge. This variant is not observed in large population cohorts (Lek et al., 2016). The c.430_432del AAC results in the deletion of a single amino acid residue, asparagine 144, and does not results in a shift in reading frame, an abnormal, truncated protein product, or loss of protein from this allele through nonsense-mediated mRNA decay. Nevertheless, in-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. - |
Dilated cardiomyopathy 1Z;C2750472:Hypertrophic cardiomyopathy 13 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 03, 2023 | This variant, c.430_432del, results in the deletion of 1 amino acid(s) of the TNNC1 protein (p.Asn144del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with TNNC1-related conditions. 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. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. ClinVar contains an entry for this variant (Variation ID: 504180). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at