chr2-178608700-T-TTCAA
Variant summary
Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001267550.2(TTN):c.52307_52310dupTTGA(p.Glu17437AspfsTer2) variant causes a frameshift, stop gained change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000027 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
TTN
NM_001267550.2 frameshift, stop_gained
NM_001267550.2 frameshift, stop_gained
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 6.22
Publications
1 publications found
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 was made for transcript
Our verdict: Pathogenic. The variant received 18 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 2-178608700-T-TTCAA is Pathogenic according to our data. Variant chr2-178608700-T-TTCAA is described in ClinVar as Pathogenic. ClinVar VariationId is 202450.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_001267550.2. You can select a different transcript below to see updated ACMG assignments.
RefSeq Transcripts
| Sel. | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| TTN | MANE Select | c.52307_52310dupTTGA | p.Glu17437AspfsTer2 | frameshift stop_gained | Exon 274 of 363 | NP_001254479.2 | Q8WZ42-12 | ||
| TTN | c.47384_47387dupTTGA | p.Glu15796AspfsTer2 | frameshift stop_gained | Exon 224 of 313 | NP_001243779.1 | Q8WZ42-1 | |||
| TTN | c.44603_44606dupTTGA | p.Glu14869AspfsTer2 | frameshift stop_gained | Exon 223 of 312 | NP_596869.4 | Q8WZ42-11 |
Ensembl Transcripts
| Sel. | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| TTN | TSL:5 MANE Select | c.52307_52310dupTTGA | p.Glu17437AspfsTer2 | frameshift stop_gained | Exon 274 of 363 | ENSP00000467141.1 | Q8WZ42-12 | ||
| TTN | TSL:1 | c.52151_52154dupTTGA | p.Glu17385AspfsTer2 | frameshift stop_gained | Exon 272 of 361 | ENSP00000408004.2 | A0A1B0GXE3 | ||
| TTN | TSL:1 | c.52031_52034dupTTGA | p.Glu17345AspfsTer2 | frameshift stop_gained | Exon 272 of 361 | ENSP00000405517.2 | A0A0C4DG59 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
33
GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000274 AC: 4AN: 1460356Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2AN XY: 726446 show subpopulations
GnomAD4 exome
Data not reliable, filtered out with message: AS_VQSR
AF:
AC:
4
AN:
1460356
Hom.:
Cov.:
32
AF XY:
AC XY:
2
AN XY:
726446
show subpopulations
African (AFR)
AF:
AC:
0
AN:
33404
American (AMR)
AF:
AC:
0
AN:
44628
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
26096
East Asian (EAS)
AF:
AC:
0
AN:
39434
South Asian (SAS)
AF:
AC:
0
AN:
86194
European-Finnish (FIN)
AF:
AC:
0
AN:
53328
Middle Eastern (MID)
AF:
AC:
0
AN:
5760
European-Non Finnish (NFE)
AF:
AC:
4
AN:
1111230
Other (OTH)
AF:
AC:
0
AN:
60282
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.488
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Age Distribution
Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
GnomAD4 genome
Cov.:
33
ClinVar
ClinVar submissions
View on ClinVar Significance:Pathogenic
Revision:criteria provided, multiple submitters, no conflicts
Pathogenic
VUS
Benign
Condition
2
-
-
Dilated cardiomyopathy 1G (2)
2
-
-
not provided (2)
1
-
-
Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G (1)
1
-
-
Cardiovascular phenotype (1)
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
PhyloP100
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
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