chr2-178591411-A-C
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Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PP2BP4
The NM_001267550.2(TTN):āc.60314T>Gā(p.Val20105Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000254 in 1,611,236 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 (ā ā ).
Frequency
Genomes: š 0.000026 ( 0 hom., cov: 32)
Exomes š: 0.000025 ( 0 hom. )
Consequence
TTN
NM_001267550.2 missense
NM_001267550.2 missense
Scores
3
4
9
Clinical Significance
Conservation
PhyloP100: 9.27
Genes affected
TTN (HGNC:12403): (titin) This gene encodes a large abundant protein of striated muscle. The product of this gene is divided into two regions, a N-terminal I-band and a C-terminal A-band. The I-band, which is the elastic part of the molecule, contains two regions of tandem immunoglobulin domains on either side of a PEVK region that is rich in proline, glutamate, valine and lysine. The A-band, which is thought to act as a protein-ruler, contains a mixture of immunoglobulin and fibronectin repeats, and possesses kinase activity. An N-terminal Z-disc region and a C-terminal M-line region bind to the Z-line and M-line of the sarcomere, respectively, so that a single titin molecule spans half the length of a sarcomere. Titin also contains binding sites for muscle associated proteins so it serves as an adhesion template for the assembly of contractile machinery in muscle cells. It has also been identified as a structural protein for chromosomes. Alternative splicing of this gene results in multiple transcript variants. Considerable variability exists in the I-band, the M-line and the Z-disc regions of titin. Variability in the I-band region contributes to the differences in elasticity of different titin isoforms and, therefore, to the differences in elasticity of different muscle types. Mutations in this gene are associated with familial hypertrophic cardiomyopathy 9, and autoantibodies to titin are produced in patients with the autoimmune disease scleroderma. [provided by RefSeq, Feb 2012]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 0 ACMG points.
PP2
Missense variant where missense usually causes diseases, TTN
BP4
Computational evidence support a benign effect (MetaRNN=0.3972312).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TTN | NM_001267550.2 | c.60314T>G | p.Val20105Gly | missense_variant | 304/363 | ENST00000589042.5 | |
TTN-AS1 | NR_038272.1 | n.3364+97A>C | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TTN | ENST00000589042.5 | c.60314T>G | p.Val20105Gly | missense_variant | 304/363 | 5 | NM_001267550.2 | P1 | |
TTN-AS1 | ENST00000659121.1 | n.417-6185A>C | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152074Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000203 AC: 5AN: 246218Hom.: 0 AF XY: 0.00000749 AC XY: 1AN XY: 133440
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GnomAD4 exome AF: 0.0000254 AC: 37AN: 1459044Hom.: 0 Cov.: 35 AF XY: 0.0000248 AC XY: 18AN XY: 725532
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GnomAD4 genome AF: 0.0000263 AC: 4AN: 152192Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74402
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ClinVar
Significance: Uncertain significance
Submissions summary: Pathogenic:1Uncertain:10
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:9
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Oct 02, 2017 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jun 10, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Jul 20, 2022 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jul 28, 2021 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Tip-toe gait Pathogenic:1
Likely pathogenic, no assertion criteria provided | clinical testing | Practice for Gait Abnormalities, David Pomarino, Competency Network Toe Walking c/o Practice Pomarino | - | Myopathy refers to diseases that affect skeletal Muscles. These diseases attack muscle fibers, making muscles weak. Inherited myopathies are often caused by inheriting an abnormal gene mutation from a parent that causes the disease. Symptoms of congenital myopathies usually start at birth or in early childhood, but may not appear until the teen years or even later in adulthood. Congenital myopathies are somewhat unique compared with other inherited myopathies, as weakness typically affects all muscles and is often not progressive. Symptoms are: Muscle weakness, most commonly of upper arms and shoulders and thighs, muscle cramps, stiffness and spasms, fatigue with exertion and lack of energy. Our patients all walk on tiptoe, so they show similar symptoms. When we genetically test them with our toe walking panel, we find that around 90 per cent of them have a genetic variant that explains their toe walking. These can be assigned, for example, to the area of myopathies (such as variants of the COL6A3 gene), the area of hereditary neuropathies (such as variants of the KMT2C gene) or the area of metabolic diseases (such as variants of the PYGM gene). In a smaller group of patients with almost identical symptoms, no abnormality is found in the genes of our panel, but spastic paraplegia can be detected. In another small group of our toe walkers, no abnormalities can be detected in the genes analysed in our toe walking panel, nor do they suffer from spastic paraplegia, as is also the case with healthy children. In contrast to these, however, they show a tiptoe gait. These patients suffer from infantile cerebral palsy, in which toe walking can also be observed. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Feb 27, 2014 | The Val17537Gly variant in TTN has now been identified by our laboratory in 1 in dividual with HCM and 1 individual with ARVC/DCM. It was absent from large popul ation studies. Computational prediction tools and conservation analysis suggest that this variant may impact the protein, though this information is not predict ive enough to determine pathogenicity. Additional information is needed to fully assess the clinical significance of the Val17537Gly variant. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Eigen
Uncertain
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Benign
T;T;T;.;T;T;T
M_CAP
Benign
D
MetaRNN
Benign
T;T;T;T;T;T;T
MetaSVM
Benign
T
MutationTaster
Benign
D;D;D;D;D;D
PrimateAI
Benign
T
PROVEAN
Pathogenic
D;D;.;.;D;D;.
REVEL
Uncertain
Sift
Benign
T;D;.;.;D;D;.
Polyphen
0.99
.;.;.;D;.;.;D
Vest4
MutPred
0.50
.;.;.;Loss of stability (P = 0.01);.;.;Loss of stability (P = 0.01);
MVP
MPC
0.46
ClinPred
T
GERP RS
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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