2-178766597-G-T
Variant names:
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4
The NM_001267550.2(TTN):c.9487C>A(p.Arg3163Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
TTN
NM_001267550.2 missense
NM_001267550.2 missense
Scores
1
11
5
Clinical Significance
Not reported in ClinVar
Conservation
PhyloP100: 3.22
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 1 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.29315582).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
TTN | NM_001267550.2 | c.9487C>A | p.Arg3163Ser | missense_variant | Exon 41 of 363 | ENST00000589042.5 | NP_001254479.2 | |
TTN | NM_133379.5 | c.9487C>A | p.Arg3163Ser | missense_variant | Exon 41 of 46 | ENST00000360870.10 | NP_596870.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
TTN | ENST00000589042.5 | c.9487C>A | p.Arg3163Ser | missense_variant | Exon 41 of 363 | 5 | NM_001267550.2 | ENSP00000467141.1 | ||
TTN | ENST00000360870.10 | c.9487C>A | p.Arg3163Ser | missense_variant | Exon 41 of 46 | 5 | NM_133379.5 | ENSP00000354117.4 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD3 exomes AF: 0.00000399 AC: 1AN: 250432Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135336
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GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1461320Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 727004
GnomAD4 exome
Data not reliable, filtered out with message: AC0
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32
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GnomAD4 genome Cov.: 32
GnomAD4 genome
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32
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ClinVar
Not reported inComputational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D;.;D;D;D;D
M_CAP
Benign
D
MetaRNN
Benign
T;T;T;T;T;T;T;T
MetaSVM
Benign
T
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D;.;.;D;D;.;D
REVEL
Uncertain
Sift
Benign
T;T;.;.;T;T;.;T
Sift4G
Uncertain
.;.;.;.;.;.;.;D
Polyphen
1.0
.;.;.;D;.;.;D;D
Vest4
MutPred
Loss of MoRF binding (P = 0.0546);.;Loss of MoRF binding (P = 0.0546);Loss of MoRF binding (P = 0.0546);.;.;Loss of MoRF binding (P = 0.0546);Loss of MoRF binding (P = 0.0546);
MVP
MPC
0.49
ClinPred
D
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at