chr2-178752043-GAA-G
Position:
Variant summary
Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_StrongBA1
The NM_133379.5(TTN):c.10361-6_10361-5del variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.13 in 1,358,708 control chromosomes in the GnomAD database, including 2,092 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.086 ( 580 hom., cov: 0)
Exomes 𝑓: 0.13 ( 1512 hom. )
Consequence
TTN
NM_133379.5 splice_region, splice_polypyrimidine_tract, intron
NM_133379.5 splice_region, splice_polypyrimidine_tract, intron
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 3.35
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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -16 ACMG points.
BP6
Variant 2-178752043-GAA-G is Benign according to our data. Variant chr2-178752043-GAA-G is described in ClinVar as [Likely_benign]. Clinvar id is 47725.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178752043-GAA-G is described in Lovd as [Benign]. Variant chr2-178752043-GAA-G is described in Lovd as [Likely_benign].
BA1
GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.117 is higher than 0.05.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
TTN | NM_001267550.2 | c.11311+1079_11311+1080del | intron_variant | ENST00000589042.5 | NP_001254479.2 | |||
TTN | NM_133379.5 | c.10361-6_10361-5del | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant | ENST00000360870.10 | NP_596870.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
TTN | ENST00000360870.10 | c.10361-6_10361-5del | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant | 5 | NM_133379.5 | ENSP00000354117 | ||||
TTN | ENST00000589042.5 | c.11311+1079_11311+1080del | intron_variant | 5 | NM_001267550.2 | ENSP00000467141 | P1 | |||
TTN-AS1 | ENST00000659121.1 | n.1224-4209_1224-4208del | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes AF: 0.0856 AC: 12065AN: 140878Hom.: 581 Cov.: 0
GnomAD3 genomes
AF:
AC:
12065
AN:
140878
Hom.:
Cov.:
0
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD4 exome AF: 0.135 AC: 163889AN: 1217776Hom.: 1512 AF XY: 0.134 AC XY: 81808AN XY: 609084
GnomAD4 exome
AF:
AC:
163889
AN:
1217776
Hom.:
AF XY:
AC XY:
81808
AN XY:
609084
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome AF: 0.0856 AC: 12068AN: 140932Hom.: 580 Cov.: 0 AF XY: 0.0860 AC XY: 5868AN XY: 68224
GnomAD4 genome
AF:
AC:
12068
AN:
140932
Hom.:
Cov.:
0
AF XY:
AC XY:
5868
AN XY:
68224
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Sep 27, 2011 | 10361-6_10361-5delTT in intron 45 of TTN: This variant is not expected to have c linical significance because it is located outside the conserved +/- 1, 2 region of the splicing consensus sequence and as part of a polyT stretch. - |
not provided Benign:1
Benign, criteria provided, single submitter | clinical testing | GeneDx | Aug 13, 2019 | This variant is associated with the following publications: (PMID: 28798025) - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
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