rs372312912
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Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate
The NM_003673.4(TCAP):c.337C>T(p.Leu113Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00017 in 1,612,972 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 Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.00012 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00017 ( 0 hom. )
Consequence
TCAP
NM_003673.4 missense
NM_003673.4 missense
Scores
8
11
Clinical Significance
Conservation
PhyloP100: 0.877
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 Likely_benign. Variant got -2 ACMG points.
BP4
?
Computational evidence support a benign effect (MetaRNN=0.23918754).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TCAP | NM_003673.4 | c.337C>T | p.Leu113Phe | missense_variant | 2/2 | ENST00000309889.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TCAP | ENST00000309889.3 | c.337C>T | p.Leu113Phe | missense_variant | 2/2 | 1 | NM_003673.4 | P1 | |
TCAP | ENST00000578283.1 | c.265C>T | p.Leu89Phe | missense_variant | 3/3 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.000125 AC: 19AN: 152248Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000144 AC: 36AN: 249588Hom.: 0 AF XY: 0.000118 AC XY: 16AN XY: 135412
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GnomAD4 exome AF: 0.000175 AC: 255AN: 1460724Hom.: 0 Cov.: 30 AF XY: 0.000182 AC XY: 132AN XY: 726702
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GnomAD4 genome ? AF: 0.000125 AC: 19AN: 152248Hom.: 0 Cov.: 32 AF XY: 0.0000672 AC XY: 5AN XY: 74372
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:10
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:4
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Nov 01, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Oct 26, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Oct 11, 2017 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Sep 18, 2023 | Reported in association with HCM although clinical and segregation data were not provided (Lopes et al., 2015); In silico analysis supports that this missense variant does not alter protein structure/function; Missense variants in this gene are often considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 25351510, 16490376) - |
Cardiovascular phenotype Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Institute of Human Genetics, Medical University Innsbruck | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 16, 2023 | The p.L113F variant (also known as c.337C>T), located in coding exon 2 of the TCAP gene, results from a C to T substitution at nucleotide position 337. The leucine at codon 113 is replaced by phenylalanine, an amino acid with highly similar properties. This alteration has been reported in a hypertrophic cardiomyopathy cohort; however, clinical details were limited (Lopes LR et al. Heart, 2015 Feb;101:294-301). This amino acid position is well conserved in available vertebrate species; however, phenylalanine is the reference amino acid in other vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jan 11, 2017 | The p.Leu113Phe variant in TCAP has been identified by our laboratory in 1 indiv idual with HCM, but has also been identified in 11/64214 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP r s372312912). This variant has also been reported in ClinVar (Variation ID: 17903 2). Computational prediction tools and conservation analysis suggest that the p .Leu113Phe variant may not impact the protein, though this information is not pr edictive enough to rule out pathogenicity. In summary, the clinical significance of the p.Leu113Phe variant is uncertain. - |
Primary familial hypertrophic cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute | - | - - |
Primary familial hypertrophic cardiomyopathy;C4225408:Hypertrophic cardiomyopathy 25 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 27, 2023 | This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 113 of the TCAP protein (p.Leu113Phe). This variant is present in population databases (rs372312912, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with TCAP-related conditions. ClinVar contains an entry for this variant (Variation ID: 179032). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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. - |
Autosomal recessive limb-girdle muscular dystrophy type 2G;C4225408:Hypertrophic cardiomyopathy 25 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jul 27, 2021 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Benign
DEOGEN2
Uncertain
D;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Benign
D
LIST_S2
Benign
T;T
M_CAP
Uncertain
D
MetaRNN
Benign
T;T
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
M;.
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;.
REVEL
Uncertain
Sift
Benign
D;.
Sift4G
Benign
T;T
Polyphen
D;.
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at