rs397516462
Variant summary
Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2
The NM_001276345.2(TNNT2):c.412-6_412-4delCCT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000813 in 1,612,288 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Consequence
NM_001276345.2 splice_region, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -16 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000460 AC: 7AN: 152220Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000116 AC: 29AN: 249246Hom.: 0 AF XY: 0.000119 AC XY: 16AN XY: 134984
GnomAD4 exome AF: 0.0000849 AC: 124AN: 1459950Hom.: 0 AF XY: 0.0000964 AC XY: 70AN XY: 726354
GnomAD4 genome AF: 0.0000460 AC: 7AN: 152338Hom.: 0 Cov.: 33 AF XY: 0.0000537 AC XY: 4AN XY: 74494
ClinVar
Submissions by phenotype
not specified Benign:2
The 382-6_382-4delCCT variant has not been reported in the literature but has be en detected by our laboratory in two Asian probands, one with HCM and one with D CM. The HCM case already had another variant thought to be causative for disease . In silico tools do not predict an impact to the splicing consensus sequence. I n summary, this data suggests this variant is likely benign. -
Variant summary: TNNT2 c.382-6_382-4delCCT alters a nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00012 in 249246 control chromosomes, predominantly at a frequency of 0.0016 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 9 fold of the estimated maximal expected allele frequency for a pathogenic variant in TNNT2 causing Cardiomyopathy phenotype (0.00018), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. c.382-6_382-4delCCT has been reported in the literature in individuals affected with Cardiomyopathy (Lakdawala_2012 and Pugh_2014) without strong evidence for causality. These reports do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 24503780, 22464770). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. -
Cardiomyopathy Benign:2
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Dilated cardiomyopathy 1D Benign:1
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Cardiomyopathy, familial restrictive, 3 Benign:1
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Hypertrophic cardiomyopathy 2 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. -
Dilated cardiomyopathy 1D;C1861864:Hypertrophic cardiomyopathy 2;C2676271:Cardiomyopathy, familial restrictive, 3 Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at