rs531432790
Positions:
Variant summary
Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2BP4_StrongBP6BS1BS2
The NM_001267550.2(TTN):c.92780T>A(p.Ile30927Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000322 in 1,613,414 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00020 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00034 ( 3 hom. )
Consequence
TTN
NM_001267550.2 missense
NM_001267550.2 missense
Scores
5
4
7
Clinical Significance
Conservation
PhyloP100: 9.32
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]
TTN-AS1 (HGNC:44124): (TTN antisense RNA 1) This gene encodes a non-coding RNA transcribed from the opposite strand to the titin gene. [provided by RefSeq, Aug 2016]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -12 ACMG points.
PP2
?
Missense variant where missense usually causes diseases, TTN
BP4
?
Computational evidence support a benign effect (MetaRNN=0.011689156).
BP6
?
Variant 2-178548846-A-T is Benign according to our data. Variant chr2-178548846-A-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 179810.We mark this variant Likely_benign, oryginal submissions are: {Benign=2, Uncertain_significance=3, Likely_benign=2}. Variant chr2-178548846-A-T is described in Lovd as [Benign].
BS1
?
Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000197 (30/152274) while in subpopulation SAS AF= 0.00601 (29/4824). AF 95% confidence interval is 0.0043. There are 0 homozygotes in gnomad4. There are 21 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
?
High Homozygotes in GnomAdExome4 at 3 AD,AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TTN | NM_001267550.2 | c.92780T>A | p.Ile30927Lys | missense_variant | 339/363 | ENST00000589042.5 | |
TTN-AS1 | NR_038272.1 | n.2043+6485A>T | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TTN | ENST00000589042.5 | c.92780T>A | p.Ile30927Lys | missense_variant | 339/363 | 5 | NM_001267550.2 | P1 | |
TTN-AS1 | ENST00000659121.1 | n.416+25210A>T | intron_variant, non_coding_transcript_variant | ||||||
ENST00000603415.1 | upstream_gene_variant |
Frequencies
GnomAD3 genomes ? AF: 0.000197 AC: 30AN: 152156Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000632 AC: 157AN: 248510Hom.: 0 AF XY: 0.000816 AC XY: 110AN XY: 134862
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GnomAD4 exome AF: 0.000335 AC: 490AN: 1461140Hom.: 3 Cov.: 34 AF XY: 0.000482 AC XY: 350AN XY: 726880
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GnomAD4 genome ? AF: 0.000197 AC: 30AN: 152274Hom.: 0 Cov.: 33 AF XY: 0.000282 AC XY: 21AN XY: 74444
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:3Benign:7
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not specified Uncertain:1Benign:4
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Nov 16, 2017 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
Benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jun 27, 2014 | The Ile28359Lys variant in TTN has not been previously reported in individuals w ith cardiomyopathy or in large population studies. Computational prediction too ls and conservation analysis do not provide strong support for or against an imp act to the protein. In summary, the clinical significance of the Ile28359Lys var iant is uncertain. - |
Benign, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Apr 01, 2018 | - - |
Primary dilated cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | research | Genetics and Genomics Program, Sidra Medicine | - | - - |
Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
Cardiomyopathy Benign:1
Benign, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Apr 12, 2018 | - - |
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 11, 2019 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, 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
Pathogenic
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D;.;D;D;D
M_CAP
Benign
D
MetaRNN
Benign
T;T;T;T;T;T;T
MetaSVM
Benign
T
MutationTaster
Benign
D;D;D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D;.;.;D;D;.
REVEL
Uncertain
Sift
Uncertain
D;D;.;.;D;D;.
Polyphen
1.0
.;.;.;D;.;.;D
Vest4
MutPred
0.73
.;.;.;Gain of disorder (P = 0.0045);.;.;Gain of disorder (P = 0.0045);
MVP
MPC
0.60
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