2-178679958-CTCTTCT-CTCTTCTTCT
Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PM4_SupportingBP6BS1BS2
The NM_001267550.2(TTN):c.33513_33515dupAGA(p.Glu11172dup) variant causes a disruptive inframe insertion change. The variant allele was found at a frequency of 0.0162 in 1,613,012 control chromosomes in the GnomAD database, including 231 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_001267550.2 disruptive_inframe_insertion
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
TTN | NM_001267550.2 | c.33513_33515dupAGA | p.Glu11172dup | disruptive_inframe_insertion | Exon 140 of 363 | ENST00000589042.5 | NP_001254479.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
TTN | ENST00000589042.5 | c.33513_33515dupAGA | p.Glu11172dup | disruptive_inframe_insertion | Exon 140 of 363 | 5 | NM_001267550.2 | ENSP00000467141.1 |
Frequencies
GnomAD3 genomes AF: 0.0111 AC: 1687AN: 151900Hom.: 10 Cov.: 32
GnomAD3 exomes AF: 0.0113 AC: 2798AN: 248470Hom.: 22 AF XY: 0.0115 AC XY: 1554AN XY: 134786
GnomAD4 exome AF: 0.0167 AC: 24446AN: 1460994Hom.: 221 Cov.: 32 AF XY: 0.0164 AC XY: 11903AN XY: 726796
GnomAD4 genome AF: 0.0111 AC: 1687AN: 152018Hom.: 10 Cov.: 32 AF XY: 0.0101 AC XY: 750AN XY: 74328
ClinVar
Submissions by phenotype
not specified Uncertain:1Benign:8
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Glu9928dup in exon 137 of TTN: This variant is not expected to have clinical sig nificance because it has been identified in 1.6% (131/7868) of European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS/). -
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Variant summary: TTN c.29781_29783dupAGA (p.Glu9928dup) results in an in-frame duplication in exon 137 of the encoded protein. The variant allele was found at a frequency of 0.011 in 248470 control chromosomes in the gnomAD database, including 22 homozygotes. The observed variant frequency is approximately 18.0 fold of the estimated maximal expected allele frequency for a pathogenic variant in TTN causing Cardiomyopathy phenotype (0.00063), strongly suggesting that the variant is benign. To our knowledge, no conclusive occurrence of c.29781_29783dupAGA in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Co-occurrences with other pathogenic/likely pathogenic variant(s) have been reported in the literature as well as at our laboratory (example DSP c.939+1G>A (Pugh_2014); TTN c.34782_34785delTTGT, p.Cys11595fs*9, our laboratory), providing supporting evidence for a benign role. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. -
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not provided Benign:4
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TTN: PM4:Supporting, BS1, BS2 -
Ventricular fibrillation, paroxysmal familial, type 1 Uncertain:1
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Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G Benign:1
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Cardiomyopathy Benign:1
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Cardiovascular phenotype Benign:1
This alteration is classified as benign based on a combination of the following: 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. -
Primary dilated cardiomyopathy;C1142166:Brugada syndrome Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at