2-178541317-C-G
Variant summary
Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS1
The NM_001267550.2(TTN):āc.97760G>Cā(p.Arg32587Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000341 in 1,546,346 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R32587H) has been classified as Likely benign.
Frequency
Consequence
NM_001267550.2 missense
Scores
Clinical Significance
Conservation
Publications
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ACMG classification
Our verdict: Benign. The variant received -9 ACMG points.
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.97760G>C | p.Arg32587Pro | missense | Exon 350 of 363 | NP_001254479.2 | ||
| TTN | NM_001256850.1 | c.92837G>C | p.Arg30946Pro | missense | Exon 300 of 313 | NP_001243779.1 | |||
| TTN | NM_133378.4 | c.90056G>C | p.Arg30019Pro | missense | Exon 299 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.97760G>C | p.Arg32587Pro | missense | Exon 350 of 363 | ENSP00000467141.1 | ||
| TTN | ENST00000446966.2 | TSL:1 | c.97604G>C | p.Arg32535Pro | missense | Exon 348 of 361 | ENSP00000408004.2 | ||
| TTN | ENST00000436599.2 | TSL:1 | c.97484G>C | p.Arg32495Pro | missense | Exon 348 of 361 | ENSP00000405517.2 |
Frequencies
GnomAD3 genomes 0.00179 AC: 272AN: 152132Hom.: 0 Cov.: 33 show subpopulations
GnomAD2 exomes AF: 0.000393 AC: 66AN: 167792 AF XY: 0.000339 show subpopulations
GnomAD4 exome AF: 0.000183 AC: 255AN: 1394096Hom.: 0 Cov.: 31 AF XY: 0.000153 AC XY: 105AN XY: 686992 show subpopulations
Age Distribution
GnomAD4 genome 0.00179 AC: 272AN: 152250Hom.: 0 Cov.: 33 AF XY: 0.00153 AC XY: 114AN XY: 74442 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
not specified Benign:6
Variant summary: TTN c.90056G>C (p.Arg30019Pro) results in a non-conservative amino acid change located in the A-band region of the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00039 in 167792 control chromosomes, predominantly at a frequency of 0.0055 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 14-fold of the estimated maximal expected allele frequency for a pathogenic variant in TTN causing Dilated Cardiomyopathy phenotype (0.00039), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. To our knowledge, no occurrence of c.90056G>C in individuals affected with Dilated Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Six ClinVar submitters (evaluation after 2014) cite the variant as benign/likely benign and one ClinVar submitter (evaluation after 2014) cites it as uncertain significance. Based on the evidence outlined above, the variant was classified as benign.
p.Arg30019Pro in exon 299 of TTN: This variant is not expected to have clinical significance because it has been identified in 0.9% (28/2972) of African chromos omes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs55704830).
not provided Benign:4
This variant is associated with the following publications: (PMID: 23861362)
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.
Cardiovascular phenotype Uncertain:1
The p.R30019P variant (also known as c.90056G>C) is located in coding exon 298 of the TTNgene. This alteration results from a G to C substitution at nucleotide position 90056. The arginine at codon 30019 is replaced by proline, an amino acid with dissimilar properties. This alteration was reported in a cohort of individuals enrolled in the ClinSeq project in 2/1506 alleles (0.13%) and classified aslikelynot pathogenic in this publication. Another alteration at this position, p.R30019H, was detected in 4/1508 (0.26%) of alleles in this cohort(Ng D et al.Circ Cardiovasc Genet.2013;6:337-346). This variant was not reported in population-based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), the 1000 Genomes Project and the NHLBI Exome Sequencing Project (ESP). In the ESP, this variant was not reported in 6058 samples (12116 alleles) with coverage at this position. However, p.R30019H was reported in the ESP and 1000 Genomes with overall frequencies of 0.37% (45/12116) and 0.09% (2/2184), respectively. Based on protein sequence alignment, this amino acid position isconserved through amphibians, but is not conserved throughout available vertebrate species. In addition, this alteration is predicted to be possibly damaging by PolyPhen analysis. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear.
Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G Benign:1
Cardiomyopathy Benign:1
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
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at