chr2-178565431-T-C
Variant summary
Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2
The NM_001267550.2(TTN):āc.80701A>Gā(p.Ile26901Val) variant causes a missense change. The variant allele was found at a frequency of 0.000927 in 1,613,444 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_001267550.2 missense
Scores
Clinical Significance
Conservation
Publications
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ACMG classification
Our verdict: Benign. The variant received -13 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| TTN | NM_001267550.2 | c.80701A>G | p.Ile26901Val | missense_variant | Exon 326 of 363 | ENST00000589042.5 | NP_001254479.2 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| TTN | ENST00000589042.5 | c.80701A>G | p.Ile26901Val | missense_variant | Exon 326 of 363 | 5 | NM_001267550.2 | ENSP00000467141.1 |
Frequencies
GnomAD3 genomes 0.000993 AC: 151AN: 152080Hom.: 2 Cov.: 33 show subpopulations
GnomAD2 exomes AF: 0.00162 AC: 403AN: 248414 AF XY: 0.00165 show subpopulations
GnomAD4 exome AF: 0.000920 AC: 1344AN: 1461246Hom.: 10 Cov.: 37 AF XY: 0.000955 AC XY: 694AN XY: 726928 show subpopulations
Age Distribution
GnomAD4 genome 0.000992 AC: 151AN: 152198Hom.: 2 Cov.: 33 AF XY: 0.000981 AC XY: 73AN XY: 74418 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
not specified Uncertain:2Benign:7
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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. -
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The p.Ile24333Val variant in TTN is classified as likely benign because it has been identified in 3.1% (326/10344) of Ashkenazi Jewish chromosomes (including 1 homozygote) and 0.04% (59/127920) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). Additionally, isoleucine (Ile) at position 24333 is not conserved in evolution and multiple birds and reptiles carry a valine (Val) at this position. Computational prediction tools predict that this variant does not impact the protein. ACMG/AMP Criteria applied: BS1, BP4. -
Variant summary: TTN c.72997A>G (p.Ile24333Val) results in a conservative amino acid change located in the A-band region (cardiodb.org) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0016 in 248414 control chromosomes in the gnomAD database, including 1 homozygote. The observed variant frequency is approximately 4.2- fold the estimated maximal expected allele frequency for a pathogenic variant in TTN causing Dilated Cardiomyopathy phenotype (0.00039), strongly suggesting that the variant is benign. c.72997A>G has been reported in the literature in individuals affected with Cardiomyopathy (e.g. Pugh_2014, Campuzano_2015, Restrepo-Cordoba_2017). These reports do not provide unequivocal conclusions about association of the variant with Dilated Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Ten other ClinVar submitters (evaluation after 2014) have cited the variant as benign/likely benign (n=8) and uncertain significance (n=2). 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: BP4, BS1, BS2 -
TTN-related disorder Benign:1Other:1
Variant interpretted as Uncertain significance and reported on 07-09-2015 by Lab or GTR ID 500060. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -
This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
Autosomal recessive limb-girdle muscular dystrophy type 2J Uncertain:1
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Dilated cardiomyopathy 1G Uncertain:1
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Early-onset myopathy with fatal cardiomyopathy Uncertain:1
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
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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Myopathy, myofibrillar, 9, with early respiratory failure Benign:1
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Tibial muscular dystrophy Benign:1
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Primary dilated cardiomyopathy Benign:1
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Cardiovascular phenotype Benign:1
This alteration is classified as 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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at