NM_001267550.2:c.54941_54943delAAG
Variant summary
Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PM4_Supporting
The NM_001267550.2(TTN):c.54941_54943delAAG(p.Glu18314del) variant causes a disruptive inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,460,306 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000021 ( 0 hom. )
Consequence
TTN
NM_001267550.2 disruptive_inframe_deletion
NM_001267550.2 disruptive_inframe_deletion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 7.97
Publications
0 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: Uncertain_significance. The variant received 3 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PM4
Nonframeshift variant in NON repetitive region in NM_001267550.2. Strenght limited to Supporting due to length of the change: 1aa.
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
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| TTN | NM_001267550.2 | MANE Select | c.54941_54943delAAG | p.Glu18314del | disruptive_inframe_deletion | Exon 283 of 363 | NP_001254479.2 | ||
| TTN | NM_001256850.1 | c.50018_50020delAAG | p.Glu16673del | disruptive_inframe_deletion | Exon 233 of 313 | NP_001243779.1 | |||
| TTN | NM_133378.4 | c.47237_47239delAAG | p.Glu15746del | disruptive_inframe_deletion | Exon 232 of 312 | NP_596869.4 |
Ensembl Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| TTN | ENST00000589042.5 | TSL:5 MANE Select | c.54941_54943delAAG | p.Glu18314del | disruptive_inframe_deletion | Exon 283 of 363 | ENSP00000467141.1 | ||
| TTN | ENST00000446966.2 | TSL:1 | c.54785_54787delAAG | p.Glu18262del | disruptive_inframe_deletion | Exon 281 of 361 | ENSP00000408004.2 | ||
| TTN | ENST00000436599.2 | TSL:1 | c.54665_54667delAAG | p.Glu18222del | disruptive_inframe_deletion | Exon 281 of 361 | ENSP00000405517.2 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1460306Hom.: 0 AF XY: 0.00000138 AC XY: 1AN XY: 726400 show subpopulations
GnomAD4 exome
AF:
AC:
3
AN:
1460306
Hom.:
AF XY:
AC XY:
1
AN XY:
726400
show subpopulations
African (AFR)
AF:
AC:
0
AN:
33406
American (AMR)
AF:
AC:
0
AN:
44616
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
26096
East Asian (EAS)
AF:
AC:
0
AN:
39450
South Asian (SAS)
AF:
AC:
0
AN:
86176
European-Finnish (FIN)
AF:
AC:
0
AN:
53340
Middle Eastern (MID)
AF:
AC:
0
AN:
5756
European-Non Finnish (NFE)
AF:
AC:
3
AN:
1111170
Other (OTH)
AF:
AC:
0
AN:
60296
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.442
Heterozygous variant carriers
0
0
1
1
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2
0.00
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0.60
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0.95
Allele balance
Age Distribution
Exome Het
Variant carriers
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10
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Age
GnomAD4 genome
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G Uncertain:1
Oct 14, 2017
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing
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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