17-39665391-CG-C
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_003673.4(TCAP):c.34del(p.Glu12ArgfsTer17) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. S11S) has been classified as Likely benign.
Frequency
Genomes: not found (cov: 32)
Consequence
TCAP
NM_003673.4 frameshift
NM_003673.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: -3.58
Genes affected
TCAP (HGNC:11610): (titin-cap) Sarcomere assembly is regulated by the muscle protein titin. Titin is a giant elastic protein with kinase activity that extends half the length of a sarcomere. It serves as a scaffold to which myofibrils and other muscle related proteins are attached. This gene encodes a protein found in striated and cardiac muscle that binds to the titin Z1-Z2 domains and is a substrate of titin kinase, interactions thought to be critical to sarcomere assembly. Mutations in this gene are associated with limb-girdle muscular dystrophy type 2G. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 ACMG points.
PVS1
?
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 36 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 17-39665391-CG-C is Pathogenic according to our data. Variant chr17-39665391-CG-C is described in ClinVar as [Pathogenic]. Clinvar id is 1459213.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TCAP | NM_003673.4 | c.34del | p.Glu12ArgfsTer17 | frameshift_variant | 1/2 | ENST00000309889.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TCAP | ENST00000309889.3 | c.34del | p.Glu12ArgfsTer17 | frameshift_variant | 1/2 | 1 | NM_003673.4 | P1 | |
TCAP | ENST00000578283.1 | c.34del | p.Glu12ArgfsTer17 | frameshift_variant | 1/3 | 5 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Primary familial hypertrophic cardiomyopathy;C4225408:Hypertrophic cardiomyopathy 25 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 09, 2022 | For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the TCAP protein in which other variant(s) (p.Gln53*) have been determined to be pathogenic (PMID: 10655062, 23479141, 25298746). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 1459213). This variant has not been reported in the literature in individuals affected with TCAP-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Glu12Argfs*17) in the TCAP gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 156 amino acid(s) of the TCAP protein. - |
Computational scores
Source:
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Calibrated prediction
Score
Prediction
Splicing
Name
Calibrated prediction
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Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
No publications associated with this variant yet.