rs869312117
Variant summary
Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001267550.2(TTN):c.78095_78098delGAAA(p.Arg26032ThrfsTer41) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,174 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Consequence
TTN
NM_001267550.2 frameshift
NM_001267550.2 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 7.97
Publications
4 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 2-178568033-GTTTC-G is Pathogenic according to our data. Variant chr2-178568033-GTTTC-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 223384.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.78095_78098delGAAA | p.Arg26032ThrfsTer41 | frameshift | Exon 326 of 363 | NP_001254479.2 | Q8WZ42-12 | ||
| TTN | c.73172_73175delGAAA | p.Arg24391ThrfsTer41 | frameshift | Exon 276 of 313 | NP_001243779.1 | Q8WZ42-1 | |||
| TTN | c.70391_70394delGAAA | p.Arg23464ThrfsTer41 | frameshift | Exon 275 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.78095_78098delGAAA | p.Arg26032ThrfsTer41 | frameshift | Exon 326 of 363 | ENSP00000467141.1 | Q8WZ42-12 | ||
| TTN | TSL:1 | c.77939_77942delGAAA | p.Arg25980ThrfsTer41 | frameshift | Exon 324 of 361 | ENSP00000408004.2 | A0A1B0GXE3 | ||
| TTN | TSL:1 | c.77819_77822delGAAA | p.Arg25940ThrfsTer41 | frameshift | Exon 324 of 361 | ENSP00000405517.2 | A0A0C4DG59 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
33
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461174Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 726866 show subpopulations
GnomAD4 exome
AF:
AC:
1
AN:
1461174
Hom.:
AF XY:
AC XY:
0
AN XY:
726866
show subpopulations
African (AFR)
AF:
AC:
0
AN:
33442
American (AMR)
AF:
AC:
0
AN:
44684
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
26122
East Asian (EAS)
AF:
AC:
0
AN:
39602
South Asian (SAS)
AF:
AC:
0
AN:
86250
European-Finnish (FIN)
AF:
AC:
0
AN:
53370
Middle Eastern (MID)
AF:
AC:
0
AN:
5760
European-Non Finnish (NFE)
AF:
AC:
1
AN:
1111608
Other (OTH)
AF:
AC:
0
AN:
60336
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.525
Heterozygous variant carriers
0
0
1
1
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2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Age Distribution
Exome Het
Variant carriers
0
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10
<30
30-35
35-40
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>80
Age
GnomAD4 genome
GnomAD4 genome
Cov.:
33
ClinVar
ClinVar submissions
View on ClinVar Significance:Pathogenic/Likely pathogenic
Revision:criteria provided, multiple submitters, no conflicts
Pathogenic
VUS
Benign
Condition
1
-
-
Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G (1)
1
-
-
Primary dilated cardiomyopathy (1)
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
PhyloP100
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
Publications
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