rs200875379
Variant summary
Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP2BP4_StrongBP6_Very_StrongBS1
The NM_001267550.2(TTN):c.91589C>T(p.Pro30530Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000179 in 1,611,872 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.0010 ( 1 hom., cov: 33)
Exomes 𝑓: 0.000089 ( 0 hom. )
Consequence
TTN
NM_001267550.2 missense
NM_001267550.2 missense
Scores
2
6
8
Clinical Significance
Conservation
PhyloP100: 6.68
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 Benign. Variant got -15 ACMG points.
PP2
?
Missense variant where missense usually causes diseases, TTN
BP4
?
Computational evidence support a benign effect (MetaRNN=0.0075724423).
BP6
?
Variant 2-178550249-G-A is Benign according to our data. Variant chr2-178550249-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 196156.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178550249-G-A is described in Lovd as [Benign]. Variant chr2-178550249-G-A is described in Lovd as [Likely_benign].
BS1
?
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00104 (159/152164) while in subpopulation AFR AF= 0.00368 (153/41528). AF 95% confidence interval is 0.00321. There are 1 homozygotes in gnomad4. There are 68 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TTN | NM_001267550.2 | c.91589C>T | p.Pro30530Leu | missense_variant | 337/363 | ENST00000589042.5 | |
TTN-AS1 | NR_038272.1 | n.2043+7888G>A | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TTN | ENST00000589042.5 | c.91589C>T | p.Pro30530Leu | missense_variant | 337/363 | 5 | NM_001267550.2 | P1 | |
ENST00000603415.1 | n.1366G>A | non_coding_transcript_exon_variant | 1/1 | ||||||
TTN-AS1 | ENST00000659121.1 | n.416+26613G>A | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes ? AF: 0.00105 AC: 159AN: 152046Hom.: 1 Cov.: 33
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GnomAD3 exomes AF: 0.000295 AC: 73AN: 247692Hom.: 0 AF XY: 0.000275 AC XY: 37AN XY: 134406
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GnomAD4 exome AF: 0.0000891 AC: 130AN: 1459708Hom.: 0 Cov.: 32 AF XY: 0.0000950 AC XY: 69AN XY: 725982
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GnomAD4 genome ? AF: 0.00104 AC: 159AN: 152164Hom.: 1 Cov.: 33 AF XY: 0.000914 AC XY: 68AN XY: 74390
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ClinVar
Significance: Likely benign
Submissions summary: Benign:10
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:3
Likely benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Sep 18, 2014 | - - |
Benign, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Likely benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Nov 27, 2015 | p.Pro27962Leu in exon 286 of TTN: This variant is not expected to have clinical significance because it has been identified in 0.43% (41/9640) of African chromo somes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs200875379). - |
not provided Benign:3
Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Feb 01, 2021 | - - |
Likely benign, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
TTN-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Apr 02, 2019 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 24, 2024 | - - |
Arrhythmogenic right ventricular cardiomyopathy Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego | Jan 03, 2018 | - - |
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 26, 2013 | This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D;.;D;D;D
M_CAP
Uncertain
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
Uncertain
D;D;.;.;D;D;.
Polyphen
0.80
.;.;.;P;.;.;P
Vest4
MVP
MPC
0.14
ClinPred
T
GERP RS
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