rs727505237
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Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS1
The NM_003280.3(TNNC1):c.203-10C>G variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,613,172 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000027 ( 0 hom. )
Consequence
TNNC1
NM_003280.3 splice_polypyrimidine_tract, intron
NM_003280.3 splice_polypyrimidine_tract, intron
Scores
2
Splicing: ADA: 0.001116
2
Clinical Significance
Conservation
PhyloP100: 2.20
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]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -9 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.85).
BP6
?
Variant 3-52451868-G-C is Benign according to our data. Variant chr3-52451868-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 179947.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=1}.
BS1
?
Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0000131 (2/152266) while in subpopulation EAS AF= 0.000386 (2/5178). AF 95% confidence interval is 0.0000683. There are 0 homozygotes in gnomad4. There are 2 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TNNC1 | NM_003280.3 | c.203-10C>G | splice_polypyrimidine_tract_variant, intron_variant | ENST00000232975.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TNNC1 | ENST00000232975.8 | c.203-10C>G | splice_polypyrimidine_tract_variant, intron_variant | 1 | NM_003280.3 | P1 | |||
TNNC1 | ENST00000496590.1 | c.71-10C>G | splice_polypyrimidine_tract_variant, intron_variant | 2 | |||||
TNNC1 | ENST00000461086.1 | n.124C>G | non_coding_transcript_exon_variant | 1/2 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152148Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251214Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135840
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GnomAD4 exome AF: 0.00000274 AC: 4AN: 1460906Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1AN XY: 726816
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GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152266Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74448
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Dec 31, 2014 | The c.203-10C>G variant in TNNC1 has been identified in 1 individual with HCM ( LMM, unpublished data). It has not been observed in large population studies. Th is variant is located in the 3' splice region. Computational tools do not sugges t an impact to splicing. However, this information is not predictive enough to r ule out pathogenicity. In summary, the clinical significance of the c.203-10C>G variant is uncertain. - |
Cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Dec 17, 2018 | - - |
Dilated cardiomyopathy 1Z;C2750472:Hypertrophic cardiomyopathy 13 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Aug 23, 2023 | - - |
Computational scores
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Name
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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dbscSNV1_ADA
Benign
dbscSNV1_RF
Benign
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at