chr2-178773588-G-T
Position:
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 3P and 3B. PM2PP2BP4BP6_Moderate
The NM_001267550.2(TTN):c.7468C>A(p.Arg2490Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2490H) has been classified as Uncertain significance.
Frequency
Genomes: not found (cov: 32)
Consequence
TTN
NM_001267550.2 missense
NM_001267550.2 missense
Scores
5
5
6
Clinical Significance
Conservation
PhyloP100: 4.60
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.
PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant where missense usually causes diseases, TTN
BP4
Computational evidence support a benign effect (MetaRNN=0.35984433).
BP6
Variant 2-178773588-G-T is Benign according to our data. Variant chr2-178773588-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 671276.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TTN | NM_001267550.2 | c.7468C>A | p.Arg2490Ser | missense_variant | 32/363 | ENST00000589042.5 | |
TTN | NM_133379.5 | c.7468C>A | p.Arg2490Ser | missense_variant | 32/46 | ENST00000360870.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TTN | ENST00000589042.5 | c.7468C>A | p.Arg2490Ser | missense_variant | 32/363 | 5 | NM_001267550.2 | P1 | |
TTN | ENST00000360870.10 | c.7468C>A | p.Arg2490Ser | missense_variant | 32/46 | 5 | NM_133379.5 | ||
TTN-AS1 | ENST00000659121.1 | n.1653+253G>T | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Cov.: 33
GnomAD4 exome
Cov.:
33
GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Likely benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not provided Benign:1
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Jun 11, 2018 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
CADD
Benign
DANN
Benign
Eigen
Pathogenic
Eigen_PC
Pathogenic
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
MutationTaster
Benign
D;N;N;N;N;N;N
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D;.;.;D;D;.;D
REVEL
Uncertain
Sift
Benign
D;T;.;.;D;D;.;D
Polyphen
1.0, 1.0
.;.;.;D;.;.;D;D
Vest4
MutPred
Loss of MoRF binding (P = 0.04);.;Loss of MoRF binding (P = 0.04);Loss of MoRF binding (P = 0.04);.;.;Loss of MoRF binding (P = 0.04);Loss of MoRF binding (P = 0.04);
MVP
MPC
0.47
ClinPred
T
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