3-52451851-G-A
Variant summary
Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2
The NM_003280.3(TNNC1):c.210C>T(p.Gly70Gly) variant causes a synonymous change. The variant allele was found at a frequency of 0.000193 in 1,613,860 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
Consequence
NM_003280.3 synonymous
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -13 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
TNNC1 | ENST00000232975.8 | c.210C>T | p.Gly70Gly | synonymous_variant | Exon 4 of 6 | 1 | NM_003280.3 | ENSP00000232975.3 | ||
TNNC1 | ENST00000496590.1 | c.78C>T | p.Gly26Gly | synonymous_variant | Exon 3 of 4 | 2 | ENSP00000420596.1 | |||
TNNC1 | ENST00000461086.1 | n.141C>T | non_coding_transcript_exon_variant | Exon 1 of 2 | 2 |
Frequencies
GnomAD3 genomes AF: 0.0000986 AC: 15AN: 152148Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000115 AC: 29AN: 251364Hom.: 0 AF XY: 0.0000957 AC XY: 13AN XY: 135886
GnomAD4 exome AF: 0.000203 AC: 296AN: 1461712Hom.: 0 Cov.: 31 AF XY: 0.000197 AC XY: 143AN XY: 727156
GnomAD4 genome AF: 0.0000986 AC: 15AN: 152148Hom.: 0 Cov.: 33 AF XY: 0.0000942 AC XY: 7AN XY: 74316
ClinVar
Submissions by phenotype
not provided Uncertain:1Benign:2
TNNC1: BP4 -
The TNNC1 p.Gly70Gly variant was not identified in the literature nor was it identified in LOVD 3.0. The variant was identified in dbSNP (ID: rs141505676) and ClinVar (classified as uncertain significance by Illumina and Invitae and as likely benign by Laboratory for Molecular Medicine). The variant was identified in control databases in 32 of 282728 chromosomes at a frequency of 0.0001132 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 30 of 129090 chromosomes (freq: 0.000232), Other in 1 of 7220 chromosomes (freq: 0.000139) and East Asian in 1 of 19952 chromosomes (freq: 0.00005), but was not observed in the African, Latino, Ashkenazi Jewish, European (Finnish), or South Asian populations. The p.Gly70Gly variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. However, 4 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing and the creation of a new 5' splice site. However, this has not been confirmed by RNA analysis and is not predictive enough to assume pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -
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Hypertrophic cardiomyopathy 13 Uncertain:1
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Cardiomyopathy Uncertain:1
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Dilated cardiomyopathy 1Z Uncertain:1
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
not specified Benign:1
Gly70Gly in exon 4 of TNNC1: This variant is not expected to have clinical signi ficance because it does not alter an amino acid residue and is not located withi n the splice consensus sequence. It has been identified in 2/7020 European Ameri can chromosomes from a broad population by the NHLBI Exome Sequencing Project (h ttp://evs.gs.washington.edu/EVS; dbSNP rs141505676). Gly70Gly in exon 4 of TNNC 1 (rs141505676; allele frequency = 2/7020) ** -
Dilated cardiomyopathy 1Z;C2750472:Hypertrophic cardiomyopathy 13 Benign:1
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Cardiovascular phenotype Benign:1
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at